Immunoproteasome assembly in the brain of LCMV-infected mice


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KREMER, Marcel, 2009. Immunoproteasome assembly in the brain of LCMV-infected mice [Dissertation]. Konstanz: University of Konstanz

@phdthesis{Kremer2009Immun-8818, title={Immunoproteasome assembly in the brain of LCMV-infected mice}, year={2009}, author={Kremer, Marcel}, address={Konstanz}, school={Universität Konstanz} }

2009 Kremer, Marcel Tissue inflammation is usually characterized by the cytokine-mediated replacement of constitutive proteasomes by immunoproteasomes that finally leads to the optimised generation of immunogenic epitopes for antigen presentation. The brain, however, is considered as an immuneprivileged organ, where both the special anatomy as well as active tolerance mechanisms repress the development of inflammatory responses and help to prevent immunopathological damage.<br />In this work we analysed the immunoproteasome expression in the brain and could show that intracranial LCMV-infection leads to the transcriptional induction of inducible subunits but results in the accumulation of immunoproteasomal precursors in the brain of BALB/c mice.<br />By immunohistology, we could identify microglia cells as the main producers of immunoproteasome, whereas in astrocytes immunoproteasome expression was almost exclusively restricted to the nuclei. Neurons and oligodendrocytes did not show any expression of immunoproteasome following intracranial LCMV-infection.<br />In vitro studies of IFN-g - stimulated astrocytes further support the hypothesis that the observed accumulation of immunoproteasomal precursor complexes takes place in this cell population.<br />We postulate that the distinct expression of immunoproteasome in the brain by certain cell-types and in certain compartments influences the fate of the ongoing immune response and shapes it in terms of Ag processing, Th cell differentiation and glia activation to an inflammatory shut-down and tissue repair or to detrimental, chronic inflammation and neuronal cell loss.<br />A regulated deposition of inactive immunoproteasomal intermediates in the cell nucleus of distinct cell-types, moreover, would reflect a post-translationally regulated mechanism to prevent inappropriate immunoproteasome activity and prevent immunoreactivity in the context of immune tolerance and immune suppression.<br />We also analysed the impact of a polymorphic variance at postion aa49 within the pro-sequence of human LMP7 on immunoproteasome formation. Concerning the polymorphic variance at position 49 within the pro-sequence of LMP7 we did not see any effect on the proteasome composition neither in tumor biopsies of patients with a defined LMP7 genotype nor in an in vitro transfection model.<br />In accordance with others, we therefore postulate that the observed disposition of the respective polymorphism for the outcome of certain pathologies is not associated with a modified proteasome composition and is excluding an effect of this polymorphism on immunoproteasome assembly. application/pdf Immunoproteasome assembly in the brain of LCMV-infected mice Kremer, Marcel eng 2011-03-24T17:46:41Z 2012-03-31T22:25:04Z terms-of-use Zusammenbau des Immunproteasoms im Gehirn LCMV-infizierter Mäuse

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