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Role of pathogenic auto-antibodies and innate immunity mediators in K/BxN murine model for Rheumatoid Arthritis

Role of pathogenic auto-antibodies and innate immunity mediators in K/BxN murine model for Rheumatoid Arthritis

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SOLOMON, Samuel, 2002. Role of pathogenic auto-antibodies and innate immunity mediators in K/BxN murine model for Rheumatoid Arthritis

@phdthesis{Solomon2002patho-8618, title={Role of pathogenic auto-antibodies and innate immunity mediators in K/BxN murine model for Rheumatoid Arthritis}, year={2002}, author={Solomon, Samuel}, address={Konstanz}, school={Universität Konstanz} }

Solomon, Samuel deposit-license 2002 application/pdf Rolle der pathogenen Antikörper und der angeborenen Immunität im K/BxN-Mausmodell der Rheumatoiden Arthritis 2011-03-24T17:45:09Z K/BxN is a most recent Rheumatoid Arthritis (http://www.ntsearch.com/search.php?q=Arthritis&v=53&src=zon) murine model, where on crossing the KRN-TCR transgenic mice with NOD mice, the F1 K/BxN off-spring’s develop spontaneous arthritis at about 3rd week after birth. The antigen recognized by the KRN TCR in the context of MHC-II I-Ag7 as well as the arthritogenic immunoglobulin was identified as glucose-6-phosphate isomerase (GPI)—a glycolytic enzyme that is expressed by all cells. Transferring just 100 ul of KBN sera into healthy as well as in lymphocyte deficient mice, could induced RA. Interestingly it could be demonstrated that also RA patients have autoantibodies to GPI using recombinant human GPI ELISA assays. To elucidate the reason for the pathogenicity and the epitopes of anti-GPI antibodies, recombinant mouse GPI was expressed and GPI-specific monoclonal antibodies were generated from the K/BxN mouse. The epitope of the mAbs were mapped by a combination of peptide fingerprinting western blot, high-resolution mass spectrometry and protein truncation studies. Transfer of GPI mAb pairs, which bind to different epitopes, could induce arthritis (http://www.ntsearch.com/search.php?q=arthritis&v=53&src=zon) in naive mice. Knockout mice as well in vivo blocking/inhibition studies were used to elucidate the role of innate immune mediators in K/BxN sera induced RA. Using the C4-/- mice, NOD mice and complement depletion study, it could be shown that the K/BxN antibodies does not activate the classical, but rather the alternative complement pathway to mediate RA. Studies from Cr2-/- mice showed that the complement receptors 1 and 2 have no modulatory role in K/BxN sera induced RA. On analysis of role of Fc receptors in K/BxN sera transfer induced RA, it was found that the FcgRIIb-/- mice were highly susceptible whereas FcgRIII-/- mice were completely resistant to disease. Also it could be shown that the TNFR1-/- and TNFR2-/- mice both developed severe disease on K/BxN sera transfer whereas blocking TNFa with anti-TNFa antibodies ameliorated RA, hence supporting a dual role of TNFa in RA. Mast cell degranulation and H1 histamine receptor inhibition in vivo significantly reduced inflammation in K/BxN sera induced RA, in this study. In vivo inhibition of the CXCR2 receptor led to significant reduction in RA, reflecting its important role in neutrophil recruitment. The in vivo depletion of macrophages in mice, led to complete resistance to inflammation in K/BxN sera induced RA, pointing to a key role for this cell in RA pathogenesis. In conclusion the important role for autoantibodies and innate immunity mediators in RA pathogenesis has been demonstrated from the studies in the K/BxN murine model for RA. 2011-03-24T17:45:09Z Solomon, Samuel Role of pathogenic auto-antibodies and innate immunity mediators in K/BxN murine model for Rheumatoid Arthritis eng

Dateiabrufe seit 01.10.2014 (Informationen über die Zugriffsstatistik)

Solomon01.pdf 611
Solomon02.pdf 88
Solomon07.pdf 70
Solomon06.pdf 49
Solomon09.pdf 47
Solomon04.pdf 46
Solomon05.pdf 42
Solomon08.pdf 41
Solomon03.pdf 41

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