Regulation der Apoptose in-vivo aktivierter, kultivierter antigenpräsentierender Zellen durch natürliche Killerzellen und den purinergen P2X7-Rezeptor

Genetic and acquired immune dysfunction may lead to infections and an inadequate immune defense by the adaptive immune system. Pathogen-triggered hypercytokinemia then leads to overactivation of monocytes and iDC. A central element of such pro-inflammatory phagocytes is the purinergic ion channel P2X7. In this dissertation, hemophagocytotic lymphohistiocytosis (HLH) and MAS (macrophage-activation syndromes (MAS) have been studied for functional single-nucleotide polymorphisms (SNPs) of the purinergic ion channel P2RX7 by pyrosequencing. A higher frequency of haplotypes bearing SNP489 C>T and SNP1513 A>C was found in these patients. The phagocytes with the SNP489/1513 mutated P2RX7 had a lower ion channel activity and were less susceptible to apoptosis when compared to wildtype cells. These properties may explain an inferior capacity to activate antigen specific T cells and the persistence of activated innate immune cells in vivo. Activated phagocyte cultures were also characterized for their surface antigen expression pattern and then tested for their susceptibility to cytolysis by natural killer (NK) cells. Immature DC and pro-inflammatory monocytes were found to be resistant to NK-mediated apoptosis, when CD86 was expressed at low density and when the respective iDC secreted higher amounts of IL-10. Confocal scanning microscopy was applied to study the NK cell/target interactions in greater detail. The impressive ingestion of killer effector cells was shown for the NK resistant target cells. These results contribute to our understanding, how the activation of an adaptive immune response against infections may be impaired and lead to an uncontrolled overactivation of monocytes and iDC