Role of pathogenic auto-antibodies and innate immunity mediators in K/BxN murine model for Rheumatoid Arthritis
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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.
Zusammenfassung in einer weiteren Sprache
K/BxN ist ein neues Mäusemodell der rheumatoiden Arthritis (http://www.ntsearch.com/search.php?q=Arthritis&v=53&src=zon), bei dem sich ab der 3. Woche nach der Geburt in der F1-Generation der Kreuzung von KRN-TCR transgenen Mäusen mit NOD-Mäusen spontan Arthritis entwickelt. In den K/BxN-Mäusen wurde das Antigen, das durch den KRN-TCR im Kontext mit dem MHC-II I-Ag7 und durch arthritogene Antikörper erkannt wird, als Glukose-6-Phosphate Isomerase (GPI) definiert. GPI ist ein glykolytisches Enzym, das in allen Zellen exprimiert wird. Die Übertragung von 100 µl der KBN-Seren aus erkrankten in gesunde Tiere verursacht Arthritis. Dies geschieht auch in Lymphozyten-defizienten Tieren. Interessanterweise konnte mit Hilfe des humanen rekombinanten GPI und eines GPI ELISAs gezeigt werden, dass auch RA-Patienten Autoantikörper gegen GPI bilden. Um die Ursache der Pathogenität und die Identität der Epitope der Anti-GPI-Antikörper aufzuklären, wurde recombinantes murines GPI hergestellt und GPI-spezifische monoklonale Antikörper aus erkrankten K/BxN-Mäusen gewonnen. Die Definition der Antikörper-Epitope erfolgte durch Western-Blot-Analyse mit partiell verdauter GPI, sowie mittels Massenspektrometrie. Die simultane Injektion dieser monoklonalen Antikörper, die an unterschiedliche Epitopes binden, konnte Arthritis in naiven Mäusen auslösen. In vivo Experimente mit verschiedenen Inhibitoren und verschiedenen Knockout-Mäusestämmen wurden durchgefürt, um die Rolle des angeborenen Immunsystems als Vermittler im K/BxN Modell aufzuklären. Bei Untersuchungen mit C4 -/- Mäusen, NOD-Mäusen und Complement-Depletionsversuchen konnte gezeigt werden, dass die K/BxN Antikörper nicht den klassischen, sondern den alternativen Komplementpfad aktivieren. Untersuchungen an Cr2 -/- Mäusen zeigten, dass weder CR1 noch CR2 eine essentielle Rolle bei der Arthritis im K/BxN Modell spielen. Bei der Analyse der Rolle von Fc rezepteron stellte sich heraus, dass FcgRIIb-/- Mäuse schwer krank werden, während FcgRIII-/- Mäuse vollständig geschützt sind. Darüber hinaus konnte gezeigt werden, dass TNFR1 -/- und TNFR2 -/- Mäuse verstärkt Arthritis nach K/BxN-Serum-Transfer entwickeln, während TNFa-blockierende Antikörper Arthritis verringern. Auch ist die Arthritis nach in vivo Hemmung von Mastzelldegranulierung und die Blockierung des Histamin1 Rezeptors stark reduziert. Die Hemmung des CXCR2 Rezeptors führte zu einer starken Verringerung der Arthritis, was auf eine wichtige Rolle dieses Rezeptors bei der Einwanderung von Neutrophilen schliessen lässt. Die Entfernung von Makrophagen in vivo führtezur Verhinderung der Arthritis, womit eine weitere essentielle Zellart definiert ist. Damit konnte die wichtige Rolle von Auto-Antikörpern und Mediatoren des angeborenen Immunsystems in der Pathogenese der RA in K/Bx-Maus-Modell nachgewiesen werden.
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SOLOMON, Samuel, 2002. Role of pathogenic auto-antibodies and innate immunity mediators in K/BxN murine model for Rheumatoid Arthritis [Dissertation]. Konstanz: University of KonstanzBibTex
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<dcterms:abstract xml:lang="eng">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.</dcterms:abstract>
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