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Sylvain Bougoin , Nicole Kerlero de Rosbo, Sonia Berrih-Aknin

Muscle pathophysiology : Anti-AChR antibodies increase IL-6 production by myoblasts and myotubes in vitro. Sylvain Bougoin , Nicole Kerlero de Rosbo, Sonia Berrih-Aknin UMR CNRS-UPS 8162, Centre chirurgical Marie Lannelongue, Le Plessis Robinson, France

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Sylvain Bougoin , Nicole Kerlero de Rosbo, Sonia Berrih-Aknin

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  1. Muscle pathophysiology:Anti-AChR antibodies increase IL-6 production by myoblasts and myotubes in vitro Sylvain Bougoin, Nicole Kerlero de Rosbo, Sonia Berrih-Aknin UMR CNRS-UPS 8162, Centre chirurgical Marie Lannelongue, Le Plessis Robinson, France International Conference on Myasthenia Gravis, December 1-2, 2009

  2. Understanding the consequences of the autoimmune attack on the muscle function Anti-AChRantibodies MIR : Main ImmunogenicRegion Accelerated degradation of AChR(Drachman et al. 1977) Blocking antibodies (Howard et al. 1987) Complement mediated damage (Engel et al. 1976) Control Muscle MG Muscle (Adapted from Drachman et al, 1994)

  3. Transcriptome analysis of rat and human muscle Transcriptome Rat / EAMG Rat (Feferman, Fuchs, Souroujon) Human Control / MG List of dysregulatedgenes List of dysregulatedgenes Muscle structural genesregulated Signalingpathways Ex: IL-6 Genescoding for heat-shockproteins Abs effect on IL-6 production?

  4. Why IL-6? • Important role in the immune system: •  Differentiation of the B cells (Klashman DJ. et al, 1991) •  Differentiation, proliferation and survival of lymphocytes (Smol'nikova V.V. et al, 2000) • High IL-6 gene expression and production by cultured human thymic epithelial cells from patients with myasthenia gravis (Cohen-Kaminsky S. et al, 1993) • IL-6 has a role in muscular contraction and is a regulator of Skeletal Muscle Hypertrophy (McKay R. et al, 2009; Serrano L. et al, 2008) • No MG induction in IL-6-/- mice (Deng C. et al, 2002)

  5. Methods Mab 198 • Sera (Control, SPMG, SNMG) • Mabs (198, 155) (S. Tzartos) Extracellular Intracellular Mab 155 Human myogenic cell line (LHCN) (V. Mouly ) Myoblasts Myotubes • Internalisation (Alpha-Bgtbinding) • IL-6 production (ELISA assays)

  6. Effects of patient sera on IL-6 production Kinetics of IL-6 production IL-6 production at 48 hours p<0.01 p<0.05 Patient sera induce the production of IL-6 by myoblasts Is the serum effect due toanti-AChRantibodies ?

  7. Effects of monoclonal anti-AChR antibodies on IL-6 production MAbs: monoclonal antibodies (Rat) Kinetics of IL-6 production IL-6 production at 48 hours p<0.001 p<0.01 Anti-AChR antibody 198 induces the production of IL-6 by myoblasts Is the IL-6 production due to AChR internalization?

  8. Effects of Mab anti-AChR on human myotubes AChR expression at 12 hours Kinetics of IL-6 production p<0.01 Ab 198 induces both a strong internalization and IL-6 production

  9. Effect of MG sera on surface AChR levels AChR expression Kinetics of IL-6 production CONTROLS SNMG SPMG Poea S. et al, 2000 Surprisingly, sera from patients with anti-AChR antibodies do not induce significant production of IL-6, while sera with undetectable antibodies do Production of IL-6 and internalization appear to be independent events Mechanisms involved?

  10. Work in progress: 10µM Ca2+ Release Signaling Pathways NF-κB… Il-6 production 2µM 5µM

  11. Conclusion: • Sera (Control, SPMG, SNMG) • Mabs (198, 155) (S. Tzartos) Myotubes Myoblasts IL-6 production A new action mechanism of anti-AChR on muscular cells

  12. Future work MG: Regenerative capacity of satellite cells Ca2+ Release ? ? Satellites cellsproliferation Il-6 production Cyclin D1 JAK2/STAT3 Mc Kay et al. 2009 ? Local immune role

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