TY - THES A1 - Probst, Lilli Teresa T1 - Immune cell function in the Clec16a Knock-down Mouse T1 - Immunzellfunktion in der Clec16a Knock-down Maus N2 - Genome wide association studies (GWAS) have identified Clec16a as disease suscepti-bility gene for numerous auto-immune disorders in particular type 1 diabetes. In spite of this strong genetic link, the role of Clec16a for immune regulation continues to be largely unknown. To study the function of Clec16a in an environment susceptible to autoimmune diseases a Clec16a deficient non obese diabetic (NOD) mouse strain was generated by means of lentiviral RNA interference. Clec16a knock down (KD) mice prove to be strongly protected against developing type 1 diabetes, an effect that is mediated by hyporeactive T effector cells. T cell hyporeactivity seems to result from an impairment of proximal TCR signalling and its cause is likely to be external to T cells. Given evidence on the involvement of the Clec16a Drosophila ortholog ema in endo- and autophagosomal processes, alterations in peripheral and/or central antigen presenting cells appeared to be potential reasons for the observed T cell hyporeactivity. While we are not able to identify any changes in quantity and quality of peripheral antigen presenting cells due to Clec16a silencing activation status of thymic epithelial cells in Clec16a KD mice deviates from NOD WT. The findings presented here suggest that thymic T cell development is affected by Clec16a variation. Such a relationship could explain the genetic association between Clec16a variations in humans and susceptibility to immune-mediated diseases, yet further investigations are needed to confirm this notion. N2 - Genomweite Assoziationsstudien haben Clec16a als Kandidaten-Gen für zahlreiche Autoimmunerkrankungen identifiziert, insbesondere für Diabetes Typ 1. Trotz dieser starken genetischen Assoziation ist die Rolle von Clec16a für die Regulierung des Immunsystems weitestgehend unbekannt. Um die Funktion von Clec16a in einer für Autoimmunerkrankungen prädisponierenden Umgebung zu untersuchen, wurde Clec16a im Mausmodell der non-obese diabetes (NOD) Maus mit Hilfe von lentiviraler RNA Interferenz herunterreguliert. Clec16a Knock down (KD) Mäuse zeigen eine deutlich reduzierte Inzidenz von Diabetes Typ 1, ein Effekt der durch hyporeaktive T Effektor Zellen vermittelt wird. Die verringerte Reaktivität der T Zellen ergibt sich vermutlich aus einer Beeinträchtigung des proximalen T Zell Rezeptor Signalweges. Die Ursache dafür scheint außerhalb der T-Zellen zu liegen. Studien die das Clec16a Drosophila Ortolog ema mit endo- und autophagosomalen Prozessen in Verbindung bringen, legen Veränderungen in peripheren und/ oder zentralen antigenpräsentierenden Zellen als mögliche Gründe für die beobachtete T Zell Hyporeaktivität nahe. Während infolge der Clec16a Herunterregulierung keine qualitativen und quantitativen Abweichungen in peripheren antigenpräsentierenden Zellen identifiziert werden konnten, zeigte sich ein veränderter Aktivierungsstatus bei Clec16a KD Thymusepithelzellen. Die hier vorgestellten Ergebnisse deuten an, dass die Entwicklung von T Zellen im Thymus durch das Niveau der Clec16a Expression beeinflusst wird. Solch eine Beziehung könnte die Assoziation zwischen Clec16a Varianten im Menschen und die Prädisposition für Autoimmunerkrankungen erklären. Jedoch sind weitere Untersuchungen notwendig, um diesen Zusammenhang zu bestätigen. KW - Clec16a KW - Type 1 Diabetes KW - NOD KW - autoimmunity KW - immune cell function Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122513 ER - TY - JOUR A1 - Murakawa, Yasuhiro A1 - Hinz, Michael A1 - Mothes, Janina A1 - Schuetz, Anja A1 - Uhl, Michael A1 - Wyler, Emanuel A1 - Yasuda, Tomoharu A1 - Mastrobuoni, Guido A1 - Friedel, Caroline C. A1 - Dölken, Lars A1 - Kempa, Stefan A1 - Schmidt-Supprian, Marc A1 - Blüthgen, Nils A1 - Backofen, Rolf A1 - Heinemann, Udo A1 - Wolf, Jana A1 - Scheidereit, Claus A1 - Landthaler, Markus T1 - RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-\(\kappa\)B pathway JF - Nature Communications N2 - The RNA-binding protein RC3H1 (also known as ROQUIN) promotes TNF\(\alpha\) mRNA decay via a 3'UTR constitutive decay element (CDE). Here we applied PAR-CLIP to human RC3H1 to identify ~3,800 mRNA targets with >16,000 binding sites. A large number of sites are distinct from the consensus CDE and revealed a structure-sequence motif with U-rich sequences embedded in hairpins. RC3H1 binds preferentially short-lived and DNA damage-induced mRNAs, indicating a role of this RNA-binding protein in the post-transcriptional regulation of the DNA damage response. Intriguingly, RC3H1 affects expression of the NF-\(\kappa\)B pathway regulators such as I\(\kappa\)B\(\alpha\) and A20. RC3H1 uses ROQ and Zn-finger domains to contact a binding site in the A20 3'UTR, demonstrating a not yet recognized mode of RC3H1 binding. Knockdown of RC3H1 resulted in increased A20 protein expression, thereby interfering with I\(\kappa\)B kinase and NF-\(\kappa\)B activities, demonstrating that RC3H1 can modulate the activity of the IKK/NF-\(\kappa\)B pathway. KW - large gene lists KW - decay KW - identification KW - stress KW - binding protein KW - RQQ domain KW - autoimmunity KW - complex KW - degradation KW - motifs Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151596 VL - 6 IS - 7367 ER - TY - JOUR A1 - Girschick, Hermann A1 - Wolf, Christine A1 - Morbach, Henner A1 - Hertzberg, Christoph A1 - Lee-Kirsch, Min Ae T1 - Severe immune dysregulation with neurological impairment and minor bone changes in a child with spondyloenchondrodysplasia due to two novel mutations in the ACP5 gene JF - Pediatric Rheumatology N2 - Spondyloenchondrodysplasia (SPENCD) is a rare skeletal dysplasia, characterized by metaphyseal lesions, neurological impairment and immune dysregulation associated with lupus-like features. SPENCD is caused by biallelic mutations in the ACP5 gene encoding tartrate-resistant phosphatase. We report on a child, who presented with spasticity, multisystem inflammation, autoimmunity and immunodeficiency with minimal metaphyseal changes due to compound heterozygosity for two novel ACP5 mutations. These findings extend the phenotypic spectrum of SPENCD and indicate that ACP5 mutations can cause severe immune dysregulation and neurological impairment even in the absence of metaphyseal dysplasia. KW - resistant acid phosphatase KW - expression KW - systemic lupus erythematosus KW - cerebral calcification KW - deficiency KW - autoimmunity KW - dysplasia KW - trap KW - spondyloenchondrodysplasia KW - ACP5 KW - immunodeficiency KW - type I interferonopathy Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149990 VL - 13 IS - 37 ER -