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Complement Targeted Therapy for Myasthenia Gravis Premkumar Christadoss, M.D. Department of Microbiology and Immunology University of Texas Medical Branch.

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Presentation on theme: "Complement Targeted Therapy for Myasthenia Gravis Premkumar Christadoss, M.D. Department of Microbiology and Immunology University of Texas Medical Branch."— Presentation transcript:

1 Complement Targeted Therapy for Myasthenia Gravis Premkumar Christadoss, M.D. Department of Microbiology and Immunology University of Texas Medical Branch 301 University Blvd. Galveston, Texas, USA Erdem Tüzün, M.D. Department of Neurology Istanbul Faculty of Medicine, Istanbul University Istanbul, Turkey

2 Complement system is involved in Myasthenia Gravis AChR-Ab + MuSK-Ab + ? Seronegative ? Experimental Autoimmune Myasthenia Gravis (EAMG) Active Immunization Passive Transfer Ocular EAMG model

3 1° immunization: 20  g TAChR/CFA per mouse s.c. 2° immunization: 20  g TAChR/CFA per mouse s.c. 28 days EAMG AChR Source Experimental Autoimmune Myasthenia Gravis

4 Grade 0: Normal Grade 1: Muscle weakness following exercise Grade 2: Grade 1 symptoms at rest Grade 3: Moribund Ocular muscles are rarely involved in this model

5 Immunopathogenesis of EAMG AChR NK? APC B cell IL-2 IFN-  IL  IL-1, IL-12 T helper AChR-specific memory T cell Proliferation and Differentiation IL-10, IFN- , TNF- , IL-6, IL-12, IL-2, IL-18 AChR-specific memory B cells C’ AChR-Ab producing cells Complement pathway activation Damage to the neuromuscular junction CD40L/CD40 Class II Peptide (  ) CD4 TCR B7 CD 28

6 a TAChR in CFA-BTxTAChR in CFA-C3 CFA-BTxCFA-C3 Complement on NMJ

7 normalpartialcomplete Immunization with human-AChR -subunit induces ocular symptoms

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 C4 concentrations suggesting increased complement consumption (Romi F, J Neuroimmunol, 2005) Serum immune complex (OD) Grip strength (gr) TAChR-immunized B6 mice Clinical grades Serum immune complex (OD) TAChR-immunized RIIIS/J mice

9 C1C4bC2a C3C5MAC CLASSICAL PATHWAY MBL PATHWAY ALTERNATIVE PATHWAY (C5bC9) C3b Bb C3bBb MBL MASP1 MASP2 COMPLEMENT PATHWAYS Which pathway is involved in EAMG? D COMMON PATHWAY

10 Complement KO mice are resistant to EAMG B6 imm. B6 imm. B6 imm. B6 imm. B6 imm. Lewis rats Passive

11 C1q C1qrs C4 C4bC2a C3C5MAC CLASSICAL PATHWAY MBL PATHWAY ALTERNATIVE PATHWAY C6 (C5bC6 C7C8C9) C3b Bb C3bBb MBL MASP1 MASP2 COMPLEMENT PATHWAYS C5a ? D COMMON PATHWAY

12 Complement targeted therapy for EAMG Lewis rats Passive Lewis rats Passive Lewis rats Passive Lewis rats Passive Wistar rats Passive

13 Anti-C5 complement monoclonal antibodies Eculizumab  paroxysmal nocturnal hemoglobinuria Pexelizumab  coronary heart disease ! Risk for infections !

14 Can EAMG be treated by classical pathway inhibition? C4+/+ C4+/- C4-/- Tuzun E. et al, 2003 EAMG incidence Anti-AChR IgG C4+/+C4-/- C3 IgG RED   -BTx binding GREEN  C3, or IgG deposits C4 KO mice display normal immune functions Normal cytokine production Normal lymphocyte proliferation Normal germinal center in spleen Normal lymph node cell counts Intact alternative pathway for host defense against microorganisms

15 Anti-C1q Prevents EAMG 200 μg Day μg Day μg Day μg 2 times a week – 5 weeks Tuzun E. et al., 2006 NMJ deposits Clinical incidence % pg/ml IL-6 B6 mice AChR imm.

16 Anti-C1q Treatment Prevents EAMG ( Tuzun E. et al., 2007) Grip strengths Clinical grades EAMG mice treated with 10  g anti-C1q 2 times a week-4 weeks Anti-C1q enhances serum immune complex levels Anti-C1q induces glomerular C3 and IgG deposits

17 Complement targeted therapy for EAMG B6 imm. Lewis rats Passive Lewis rats Passive Lewis rats Passive Lewis rats Passive Wistar rats Passive

18 Other targets, double hit method? Prevention – 0.01 mg IL-1ra Reduced serum C3 levels 0.01 mg IL-1raplacebo Prevention – 0.5 mg anti-IL-6 Reduced serum C1q levels 0.5 mg anti-IL-6PBS

19 Reduced serum complement levels CD59 KO FcRIII KO Reduced NMJ complement deposits IFN- KO IL-5 KO ICOS KO EAMG-resistant KO strains

20 Non-AChR Ab mediated MG, alternative pathway Leite et al., 2008  complement activating IgG1 in anti-MuSK+ and seronegative MG Shiraishi et al., 2005  2 of 8 anti-MuSK+ patients display NMJ C3 deposits FBb * * *;p=0.045

21 THANKS! UTMB Premkumar Christadoss Saini Shamsher Huan Yang Benjamin Scott Elzbieta Goluszko Jing Li Istanbul University Vuslat Yılmaz Güher Saruhan-Direskeneli Feza Deymeer Piraye Oflazer Yeşim Parman


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