Targeted delivery of CpG ODN to CD32 on human and monkey plasmacytoid dendritic cells augments IFNalpha secretion.

Item does not contain fulltextAtopic diseases are characterized by the presence of Th2 cells. Recent studies, in mice and man, demonstrated that allergen-specific Th2 responses can be shifted to Th0/Th1 responses. Plasmacytoid dendritic cells (pDCs) produce large amounts of type I interferons (IFNs) after stimulation of Toll Like Receptor 9 (TLR9) and are likely to play an important role in the reorientation of these Th2 cells. The expression of CD32a on the cell surface of pDCs makes this cell type attractive for targeted delivery of antigen and TLR agonists to revert Th2 responses. Therefore we sought to determine the efficacy of targeted delivery of CpG-C ODN to CD32a on the ability of human and monkey pDCs to secrete inflammatory cytokines. Here we demonstrate that targeted delivery of 3'-biotinylated CpG-C to CD32a on pDC induced phenotypical maturation as determined by CD80, CD83 and CD86 expression. Furthermore, targeting both monkey and human pDCs strongly augmented the secretion of IFNalpha compared to the delivery of CpG-C in an untargeted fashion (p<0.001). TLR9 induced activation hampers the ability of human pDCs to internalize CD32a. Therefore we opted for targeted delivery of CpG-ODNs to CD32a, which reduces the risk of undesired side effects of systemic TLR treatment and in addition delivers a superior signal for the activation of pDCs. This approach opens new treatment principles for allergic patients.1 oktober 201

Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase Cgamma2 that specifically increases external Ca2+ entry.

The identification of specific genetic loci that contribute to inflammatory and autoimmune diseases has proved difficult due to the contribution of multiple interacting genes, the inherent genetic heterogeneity present in human populations, and a lack of new mouse mutants. By using N-ethyl-N-nitrosourea (ENU) mutagenesis to discover new immune regulators, we identified a point mutation in the murine phospholipase Cg2 (Plcg2) gene that leads to severe spontaneous inflammation and autoimmunity. The disease is composed of an autoimmune component mediated by autoantibody immune complexes and B and T cell independent inflammation. The underlying mechanism is a gain-of-function mutation in Plcg2, which leads to hyperreactive external calcium entry in B cells and expansion of innate inflammatory cells. This mutant identifies Plcg2 as a key regulator in an autoimmune and inflammatory disease mediated by B cells and non-B, non-T haematopoietic cells and emphasizes that by distinct genetic modulation, a single point mutation can lead to a complex immunological phenotype

Een procedureel rechtvaardiger arbitragesysteem als remedie tegen kwetsende spreekkoren in voetbalstadions.

In dit experiment stond de relatie tussen rechtvaardigheid en verbale agressie jegens voetbalscheidsrechters centraal. De respondenten (N = 48 mannen; allen in meer of' mindere mate supporter van SC Heerenveen) kregen een digitaal videofragment uit een wedstrijd van SC Heerenveen te zien waarbij sprake was van een voor SC Heerenveen nadelige beslissing die correct (distributieve rechtvaardigheid) of incorrect (distributieve onrechtvaardigheid) was. Het effect van distributieve (on)rechtvaardigheid op verbale agressie werd onder drie verschillende condities van procedurele rechtvaardigheid onderzocht: het thans vigerende arbitragesysteen, het thans vigerende arbitragesysteem met een herhaling, en een nieuw, procedureel rechtvaardiger arbitragesysteem waarin de scheidsrechter gebruik maakte van videobeelden voordat hij een definitieve beslissing nam. Overeenkomistig de verwachtingen lieten de resultaten zien dat in het huidige systeem, een correcte maar voor SC Heerenveen nadelige arbitrale beslissing relatief veel verbale agressie opriep, maar alleen bij toeschouwers die zich sterk identificeerden met SC Heerenveen. Dit resultaat suggereert dat verbale agressie in voetbalstadions kan worden beteugeld door invoering van het nieuwe, procedureel rechtvaardiger arbitragesysteem