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Rozen Le Panse CNRS UMR 8162 Centre Chirurgical Marie lannelongue Le Plessis Robinson - France

Thymic changes in Myasthenia Gravis:. Involvement of chemokines in thymic hyperplasia associated with an inflammatory environment. Rozen Le Panse CNRS UMR 8162 Centre Chirurgical Marie lannelongue Le Plessis Robinson - France. International conference on Myasthenia

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Rozen Le Panse CNRS UMR 8162 Centre Chirurgical Marie lannelongue Le Plessis Robinson - France

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  1. Thymic changes in Myasthenia Gravis: Involvement of chemokines in thymic hyperplasia associated with an inflammatory environment Rozen Le Panse CNRS UMR 8162 Centre Chirurgical Marie lannelongue Le Plessis Robinson - France International conference on Myasthenia December 1-2, 2009 - Paris - France

  2. Implication of the thymus in MG Thymus AChR+ Myasthenia Gravis (MG) • AChR expression(Wakkach et al., 1996) • Anti-AChR autoreactive T cells(Melms et al., 1988) • B cells producing anti-AChR antibodies(Leprince et al., 1990 B B B B B AChR Muscle

  3. Adult control MG MG + corticoïds p<0.001 p<0.003 10 Germinal centers (CD21 labeling) 1 % of CD21+ areas Epithelial cells (keratin labeling) 0.1 0.01 Controls MG MG + Cortico Thymic hyperplasia in AChR+ MG Ectopic germinal centers (GCs) Méraouna et al., Blood 2006

  4. Stroma GCs HEVs PROX1 mRNA (AU) VEGFR3 mRNA (AU) Neoangiogenesis is associated with thymic hyperplasia MG Adult control GCs HEVs Ectopichighendothelial venules (HEVs) Lymphangiogenesis Berrih-Aknin et al., Ann. of Neurol. 2009

  5. ELISA Role of chemokine in thymic hyperplasia Thymic transcriptome analysis revealed a chemotactic signature in the hyperplastic thymus of MG patients. Chemotactic assays CXCL13 CCL21 Expression of chemokines involved in GC formation Le Panse et al., J. Immunol 2006

  6. Analysis of CXCL13 overexpression in MG Q-PCR on thymic epithelial cells Laser-capture microdissection Q-PCR on CXCL13 CXCL13 mRNA (AU) CXCL13 overexpression by thymic epithelialcells Méraouna et al., Blood 2006

  7. Generation of transgenic mice for CXCL13 • Heterozygous… Immunofluorescence Q-PCR on CXCL13 Keratin B220 Increased expression of CXCL13 and B-cellrecruitment Weiss et al., in progress

  8. VEGFR3 CCL21 Analysis of CCL21 overexpression in MG Q-PCR for PROX1 and D6 Transwell assays Immunofluorescence % of cell migration CCL21 HEVs CCL21 overexpression by lymphaticvessels Berrih-Aknin et al., Ann. of Neurol. 2009

  9. Search for chemokines on HEVs Immunofluorescence MG SDF1 Transcytosis ? HEVs Expression of SDF1 on thymic HEVs Julia Weiss : Poster 16

  10. Roles of chemokines in thymic hyperplasia B FDC GC B B B B B B B FDC B B B B B B B B B B B Lymphatic endothelial cells B B B B B B B B B B B B B B Epithelial cells B B B B B B B T T B B B B B B B B T B B B B B B B B B Tn Tn T T B B B T B B B T B B B T T T T DC Tn Tn T Tn T Tn Tn CCL21 CXCL13 Peripheral cell recruitment HEV SDF1-α RANTES (Colombarra et al., 2005) CXCL10(Feferman et al., 2003) CXCL9-CXCL11 (Transcriptomic analysis) Thymus Signals triggering these thymic dysregulations ?

  11. Microarray analysis revealed a role for IFN-I in MG Q-PCR and ELISA Microarray data -IFN -IFN Increased expression of IFN- in MG thymuses Cufi et al., in progress

  12. Roles of IFN-I on chemokine expression Lymphatic endothelial cells (Dermal LECs) Thymic epithelial cells CXCL13 CCL21 U/ml U/ml IFN-I IFN-II IFN-I IFN-II -AChR • IFN-I induces the expression of : • CXCL13 and CCL21 • -AChR IFN-I Perrine Cufi : Poster 14

  13. Poly(I:C) (µg/ml) Potential involvement of viral infection in MG TLR3 Specific effect of Poly(I:C) TLR1/2 TLR4 TLR5 TLR6/2 TLR7 TLR7/8 TLR9 Selective effect on the -AChR subunit Cufi et al., in progress

  14. Poly(I:C) Control Q-PCR on AChR subunits In vivo confirmation of Poly(I:C) effects on -AChR -AChR -AChR Thymic upregulation of -AChR expression by Poly(I:C) Cufi et al., in progress

  15. Conclusion Could a viral infection, under particular conditions, trigger thymic changes involved in MG? Thymic Hyperplasia

  16. UMR 8162 Acknowledgements WEIZMANN INSTITUTE IditShachar Frida Lantner Sonia Berrih-Aknin Nicole Kerlero de Rosbo Géraldine Cizeron-Clairac Jacky Bismuth Amel Méraouna Frédérique Truffault Julia Weiss Nathalie Ruhlman Perrine Cufi

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