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- Hennig, Janosch, 1977-
(författare)
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Structure-function studies on TRIM21/Ro52, a protein involved in autoimmune diseases
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Several members of the tripartite motif (TRIM) protein family are involvedin antiviral activity and immunity and have been linked to severaldiseases. TRIM21, the main object of this thesis, is involved in Sjögrensyndrome (SS) and systemic lupus erythematosus (SLE), where patientsoften have autoantibodies against different epitopes on TRIM21. Duringthe course of this study a role of TRIM21 in regulation of proinflammatorycytokines and autoimmunity emerged. The aim of this thesis is to providea better understanding of the structure-function relationship of TRIM21.A conformational epitope in the coiled-coil domain of TRIM21 has beencharacterized, whose autoantibodies cause congenital heart block. A widerange of biophysical methods were employed to establish a model of theprotein domain arrangement of TRIM21, and functional implications werederived. By sequence comparisons, TRIM proteins were classified into threesubgroups, sharing a conserved amphipathic helix in the region, linkingthe conserved N-terminal Zn2+-binding domains RING and B-box, calledthe RING-B-box linker (RBL). A structural dependence of this region on theRING has been observed and a model of the RING-RBL was derived frombioinformatics and proteolysis data. Anti-RING-RBL antibodies inhibit theE3 ligase activity of TRIM21 in ubiquitination. Interferon regulatory factors(IRFs), the substrate for TRIM21-dependent ubiquitination could thereforeretain their high cellular levels after stress-induced inflammation, increasingthe susceptibility to SS and SLE. According to NMR data, the antibodiesbind to the Zn2+-binding loop regions of the RING, which usually bind tothe E2 conjugating enzyme. Antibodies against the C-terminus of the RBLregion do not inhibit the E3 ligase activity.
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- Leupold, Jochen, et al.
(författare)
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Fast chemical shift mapping with multiecho balanced SSFP
- 2006
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Ingår i: Magma. - : Springer Science and Business Media LLC. - 1352-8661. ; 19:5, s. 267-273
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Tidskriftsartikel (refereegranskat)abstract
- Object: A method is proposed that provides spectroscopic images with high spatial resolution and moderate spectral resolution at very short total data acquisition times. Materials and methods: Balanced steady-state free precession (bSSFP, TrueFISP, FIESTA, b-FFE) is combined with a multiecho readout gradient and frequency-sensitive reconstruction such as Fourier reconstruction known from echo-planar spectroscopic imaging (EPSI) or matrix inversion. Balanced SSFP imaging requires short repetition times to minimize banding artefacts, thereby restricting the achievable frequency resolution. Results: Two-dimensional (2D) high-resolution spectroscopic images were produced of three H-1 resonances (water, acetone and fat) on phantoms and water/fat separation in vivo within 1-2 s. Additionally, fast P-31 spectroscopic images were acquired from a phantom consisting of two resonances within 195 ms. Conclusion: Frequency-sensitive reconstruction of multiecho bSSFP data can provide spectroscopic images with high spatial and temporal resolution while the frequency resolution is moderate at around 100 Hz. The method can also separate more than three resonances, allowing for hetero-nuclei metabolite mapping, for example C-13 and P-31.
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- Leupold, Jochen, et al.
(författare)
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Fast multiecho balanced SSFP metabolite mapping of H-1 and hyperpolarized C-13 compounds
- 2009
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Ingår i: Magma. - : Springer Science and Business Media LLC. - 1352-8661. ; 22:4, s. 251-256
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the feasibility of multiecho balanced steady-state free precession (bSSFP)-based fast chemical shift mapping hyperpolarized C-13 metabolites. The overall goal was to reduce total imaging time and to increase spatial resolution compared to common chemical shift imaging (CSI). A multiecho bSSFP sequence in combination with an iterative reconstruction algorithm was implemented. H-1 experiments were performed on phantoms and on a human volunteer in order to investigate the feasibility of the method on a system with metabolite maps that are known beforehand. C-13 experiments were performed in vivo on pigs, where CSI images were acquired also for comparison. Chemical shift images of three and four distinct H-1 resonance frequencies as well as chemical shift images of up to five hyperpolarized C-13 metabolites were successfully obtained. Fast metabolite mapping based on multiecho balanced SSFP in combination with an iterative reconstruction approach could successfully separate several H-1 resonances and hyperpolarized C-13 metabolites.
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- Ottosson, L., et al.
(författare)
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Structurally derived mutations define congenital heart block-related epitopes within the 200-239 amino acid stretch of the Ro52 protein
- 2005
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 61:2, s. 109-118
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Tidskriftsartikel (refereegranskat)abstract
- Congenital heart block is a passively transferred autoimmune condition, which affects the children of mothers with Ro/SSA autoantibodies. During pregnancy, the antibodies are transported across the placenta and affect the fetus. We have previously demonstrated that antibodies directed to the 200-239 amino acid (aa) stretch of the Ro52 component of the Ro/SSA antigen correlate with the development of congenital heart block. In this report, we investigated the antibody-antigen interaction of this target epitope in detail at a molecular and structural level. Peptides representing aa 200-239 (p200) with structurally derived mutations were synthesized to define the epitopes recognized by two Ro52 human monoclonal antibodies, S3A8 and M4H1, isolated from patient-derived phage display libraries. Analyses by ELISA, circular dichroism and MALDI-TOF-MS demonstrate that the antibody recognition is dependent on a partly a-helical fold within the putative leucine zipper of the 200-239 aa stretch and that the two human anti-p200 monoclonal antibodies, M4H1 and S3A8, recognize different epitopic structures within the p200 peptide. In addition, we investigated the representation of each fine specificity within the sera of mothers with children born with congenital heart block, and in such sera, antibodies of the S3A8 idiotype were more commonly detected and at higher levels than M4H1-like antibodies.
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- Thunman, Mikael, et al.
(författare)
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Study on the formation of open-eye and slag entrainment in gas stirred ladle
- 2007
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Ingår i: Steel Research International. - : Wiley. - 1611-3683 .- 1869-344X. ; 78:12, s. 849-856
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Tidskriftsartikel (refereegranskat)abstract
- Laboratory experiments were carried out to study the phenomena related to open-eye formation in ladle treatment. Ga-In-Sn alloy with a melting temperature of 283 K was used to simulate the liquid steel, while MgCl2-Glycerol(87%) solution as well as HCl solution were used to simulate the ladle slag. No open-eye was formed at lower gas flow rates, but, occurred when gas flow reached a critical rate. This critical gas flow rate was found to depend significantly on the height of the top liquid. No noticeable amount of top liquid was observed in any of the samples taken from the metal bulk during gas stirring. To confirm this aspect, samples of slag-metal interface were taken around the open-eye in an industrial gas stirred steel ladle. No entrapped slag droplet was found in the solidified steel within the region between the interface and 2 cm from the interface. The accordance of the laboratory and industrial results suggests that the entrainment of slag into the steel bulk around the open-eye cannot be considered as the major contribution to inclusion formation.
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