Presentation on theme: "Complement Targeted Therapy for Myasthenia Gravis"— Presentation transcript:
1 Complement Targeted Therapy for Myasthenia Gravis Erdem Tüzün, M.D.Department of NeurologyIstanbul Faculty of Medicine, Istanbul UniversityIstanbul, TurkeyPremkumar Christadoss, M.D.Department of Microbiology and ImmunologyUniversity of Texas Medical Branch301 University Blvd.Galveston, Texas, USA
2 Complement system is involved in Myasthenia GravisAChR-Ab +MuSK-Ab + ?Seronegative ?Experimental Autoimmune Myasthenia Gravis(EAMG)Active ImmunizationPassive TransferOcular EAMG model
4 Ocular muscles are rarely involved in this model Grade 0: NormalGrade 1: Muscle weakness following exerciseGrade 2: Grade 1 symptoms at restGrade 3: MoribundOcular muscles are rarely involved in this model
5 Immunopathogenesis of EAMG NK?Class IIPeptide(a )CD4TCRAChR-Abproducing cellsComplement pathway activationIL-2IFN-gIL-18B7CD 28APCT helperProliferation and DifferentiationIL-10, IFN-g, TNF-a, IL-6,IL-12, IL-2, IL-18AChRCD40L/CD40IL-1, IL-12C’C’AChR-specific memory B cellsB cellAChR-specific memory T cellDamage to the neuromuscular junction
6 Complement on NMJTAChR in CFA-BTxaTAChR in CFA-C3CFA-BTxCFA-C3
7 Immunization with human-AChR -subunit induces ocular symptoms normalpartialcomplete
8 Complement-antibody-clinical severity correlations C3 levels correlate with clinical severity of AChR-Ab-positive generalized MG patients with no treatment(Liu A, Muscle Nerve, 2009)MG patients with high AChR-Ab levels have lower C3 and C4concentrations suggesting increased complement consumption(Romi F, J Neuroimmunol, 2005)Clinical gradesSerum immune complex (OD)Grip strength (gr)Serum immune complex (OD)TAChR-immunized B6 miceTAChR-immunized RIIIS/J mice
9 C1 C4b C2a MASP1 MASP2 MBL C3 C5 MAC (C5bC9) C3b Bb C3bBb D COMPLEMENT PATHWAYSCLASSICAL PATHWAYC1C4bC2aMASP1MASP2MBLC3C5MAC(C5bC9)MBL PATHWAYCOMMON PATHWAYC3bBbC3bBbDALTERNATIVE PATHWAYWhich pathway is involved in EAMG?
10 Complement KO mice are resistant to EAMG B6imm.B6imm.B6imm.Lewis ratsPassiveB6imm.B6imm.
14 Can EAMG be treated by classical pathway inhibition? Tuzun E. et al, 2003C4+/+C4+/-C4-/-EAMG incidenceAnti-AChR IgGC4+/+C4-/-C4 KO mice display normal immune functionsNormal cytokine production Normal lymphocyte proliferation Normal germinal center in spleenNormal lymph node cell countsIntact alternative pathway for host defense against microorganismsC3IgGRED -BTx bindingGREEN C3, or IgG deposits
15 Anti-C1q Prevents EAMG B6 mice 200 μg Day -7 200 μg Day -4 100 μg 2 times a week – 5 weeksAChR imm.AChR imm.Clinical incidence %IL-6NMJ depositspg/mlAnti-C1q Prevents EAMGTuzun E. et al., 2006
16 EAMG mice treated with 10μg anti-C1q 2 times a week-4 weeks Anti-C1q enhances serum immune complex levelsClinical gradesAnti-C1q induces glomerular C3 and IgG depositsGrip strengthsAnti-C1q Treatment Prevents EAMG (Tuzun E. et al., 2007)
19 EAMG-resistant KO strains Reduced serum complement levelsCD59 KOFcRIII KOReduced NMJ complement depositsIFN- KOIL-5 KOICOS KO
20 Non-AChR Ab mediated MG, alternative pathway Leite et al., 2008 complement activating IgG1 in anti-MuSK+ and seronegative MGShiraishi et al., 2005 2 of 8 anti-MuSK+ patients display NMJ C3 depositsFBb*;p=0.045**