5-1. Review of complement system. Khadizha Emirova (eng)


Published on

Published in: Health & Medicine, Technology
  • Be the first to comment

  • Be the first to like this

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide

5-1. Review of complement system. Khadizha Emirova (eng)

  1. 1. REVIEW OF COMPLEMENT SYSTEM KHADIZHA EMIROVA (Russia) Moscow State University of Medicine and Dentistry Named after A.I.Evdokimov
  2. 2. Complement system  system of blood proteins with proteolytic activity, interacting with each other and with other proteins of the immune system required to provide antimicrobial protection (native and specific immunity)
  3. 3. Complement system  Activated by the type of enzymatic cascade reaction  The proteins of the complement system become immunological activity only under pathological conditions
  4. 4. Complement: ancient defense system Миллионы лет назад Alternative pathway Lectin pathway Classical pathway Приобретенный иммунитет 4 dapted from Fujita T, Nature Rev Immunol 2, 346-353, 2002.
  5. 5. Activation pathway of complement activation, and triggers
  6. 6. Complement components Molecular weight Serum concentration (ug/ml) Classical pathway С1 С4 С2 С3 С5 С6 С7 С8 С9 570,000 209,000 117,000 190,000 206,000 95,000 120,000 163,000 79,000 370 430 30 1,400 75 60 55 80 160 Lectin pathway MBL MASP 1 MASP 2 32,000 90,000 74,000 0,5-5,0 1,6-7,5 NC 100,000 25,000 223,000 200 1-5 25 Component Alternative pathway B D P Bellanti; IMMUNOLOGY;: Clinical Applications in Health and Disease, 2012
  7. 7. Complement system Белки системы комплемента обозначаются «С» с порядковыми номерами от 1 до 9 и буквами латинского алфавита (B, D или P) Субъединицы и фрагменты, образующиеся при расщепление компонентов комплемента, обозначаются порядковыми номерами с малыми буквами (С2а, С3b и т.д.) Активированную форму комплемента обозначают штрихом сверху над указанием компонента комплемента с его субкомпонентами (C3bC2a , С3bBb и т.д.) Если активированный фрагмент компонента комплемента, теряет свою активность, то для в обозначении добавляется «i» (С3bi)
  8. 8. Complement - always activated with further activation of the immune system triggers always active C3 + H2O An additional activation pathway microbes Alternative pathway Permanent activation of the complement system antibody microbes Classical Lectin Triggers (upper respiratory tract infection, gastroenteritis / diarrhea, pregnancy, surgery, stress, physical activity, injury) stimulate the further strengthening of the complement activation of the complement Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4(3):359-395; Walport MJ. N Engl J Med. 2001;344(14):1058-66; SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.; Rother RP et al. Nature Biotech. 2007;25(11):1256-64; Meyers G et al. Blood. 2007;110(11):Abstract 3683; Hill A et al. Br. J. Hematol. 2010;149(3):414-425;
  9. 9. Main functions of the complement system  Lysis of microbes (MAC)  Opsonisation (C3b, C4b, C1q)  Generation of an inflammatory reaction (C5a, C3a, C5b-9) – Mediator release from mast cells – Contraction of smooth muscle cells – Increased permeability of blood vessels  Chemotaxis and activation of phagocytes (C5a)  Processing of immune complexes (C3b, C4b, CR1)  Strengthening the B- and T-cell immune responses – Natural (endogenous) adjuvant effects via C3d-CD21 and iC3b-CR3 2. CR1, complement receptor type 1 1. Holers VM et al. Immunol Rev. 2008;223:300-316. 2. Zipfel PF et al. Curr Opin Nephrol Hypertens. 2010;4:372-378.
  10. 10. Complement cascade provides a variety of potential therapeutic targets Proximal Classical pathway C4 + C2 Lectin pathway CD55 C3 C4b2a C1qrs C4a C2b C3 C3H2O D+B C3bBb Ba CFI/MCP C3b C3a C3bBb3b C5 convertase C5 C5a CR3 CFI, CFH C4b2a3b Potent anaphylatoxin Chemotaxis Cell activation Pro-inflammatory Pro-thrombotic C3bi C5b C6 C7 C8 C9 C5b-9 terminal complement complex C3H20 Tickover C3b C3 C4b Weak anaphylatoxin Terminal CD55, CFH Alternative pathway Microbial opsonisation Immune complex clearance C5 convertase Cell lysis Cell activation Pro-inflammatory Pro-thrombotic
  11. 11. Membrane Attack Complex (MAC) MAC Разрушающаяся чужеродная клетка
  12. 12. Natural regulators of complement Oppression and control of the complement Activation of the complement CFH C3 CFI Factor B MCP (CD46) Factor D ТHBD antiCFH аt DAF (СD55) Protectin (СD59) Noris M, et al. Clin J Am Soc Nephrol. 2010;5:1844–1859 Noris et al NEJM 2009 Oct 22; 361(17):1676-87 12
  13. 13. Dual role of complement in the development of immunological inflammation  Too much – Causes inflammation and tissue damage (C5a and MAC)  Too little – Failure in the clearance of damaged tissue or microbes → debris or microbial components persist → (auto)immune responses develop
  14. 14. Benefits and harms of complement «Свой» Измененный «свой» защита клеток хозяина невоспалительное удаление измененных клеток хозяина regulators «Чужой» regulators активация комплемента и удаление инфекционных микроорганизиов no regulators physiological Complement terms pathological terms No regulators or defective regulators Неадекватное действие регуляторов ведет к повреждению клеток хозяина Поврежденный «свой» No regulators or defective regulators acquired regulators Неэффективное удаление измененных клеток хозяина может вести к патологии Измененный «свой» Активация комплемента и удаление инфекционных микроорганизмов Похожий на «своего» Zipfel PF, Skerka C. Nature Rev Immunol. 2009.
  15. 15. Mechanisms of discrimination between self and non-self by complement  Protective coating by sialic acid, phospholipids and GAGs (glycophorin-sialic acid on RBCs, heparan sulphate on endothelial cells) H B C3b C3b #3 #1 #2 #3 #1 #2 Non-activator surface ‘Self’ GAG, glycosaminoglycan Activator surface ‘Non-self’
  16. 16. Protected ‘self’ (non-activating surface) 1) B 2) Factor H FH I 3) 1) Inhibits factor B binding to C3b 2) Accelerates the decay of C3bBb 3) Cofactor for factor I in cleaving C3b to iC3b → inhibition of phagocytosis and killing by MAC Polyanions (GAGs, sialic acid, phospholipids) Loss of protection → attack against self tissues (innate autoreactivity) C3 Amplification B D C1q MAC Target MAC, membrane attack complex; GAG, glycosaminoglycan
  17. 17. Mechanisms of discrimination between self and non-self by complement  Membrane regulators of complement activation – CR1 (CD35) – MCP (CD46) – DAF (CD55) – Protectin (MAC inhibitor, CD59) I Bb C9 C6 C7 iC3b C3b C3b C5b C8 CR1, complement receptor type 1; MCP, membrane cofactor protein; DAF, delay-accelerating factor; MAC, membrane attack complex CD46 (MCP) CD35 (CR1) CD55 (DAF) CD59
  18. 18. The complement system Classical pathway Bacterial infections MPGN HUS LED Ag-Ab, CRP Neisseria meningitidis C4bp C1q C1rs C4, C2 H C3 D, P C3bBb C3b,B C4b2a C1 INH MASP1, 2, 3 DAF DAF, CR1 H HAE MBL Microbes Bacterial infections Lectin pathway Alternative pathway PNH CD59 Ag-Ab, antigen-antibody; CRP, C-reactive protein; MBL, mannan-binding lectin; MASP, mannose-associated serine protease; DAF, delay-accelerating factor; MPGN, membranoproliferative glomerulonephritis; aHUS, atypical haemolytic uraemic syndrome; HAE, hereditary angio-oedema; PNH, paroxysmal nocturnal haemoglobinuria Microbes LAD C3b C3bi CR3 + I Bacterial infections C5 C6 Neisseria meningitidis C7 C8 C9 Lysis
  19. 19. Failure in control → ‘innate autoreactivity’ C1-INH Factor H (N-terminus) Factor H (C-terminus) Factor I CD46 (MCP) CD55, CD59 → HAE → DDD (MPGN2), partial lipodystrophy, AMD → aHUS → aHUS → aHUS → PNH HAE, hereditary angio-oedema; DDD, dense deposit disease; MPGN, membranoproliferative glomerulonephritis; AMD, age-related macular degeneration; aHUS, atypical haemolytic uraemic syndrome; MCP, membrane cofactor protein; PNH, paroxysmal nocturnal haemoglobinuria
  20. 20. Other diseases where complement activation is involved  Cold agglutinin disease – IgM autoantibodies against RBCs  Catastrophic antiphospholipid syndrome – Antiphospholipid antibodies – Thrombotic occlusion of small blood vessels, organ failure, necrosis  Myasthenia gravis – IgG autoantibodies against AChRs  Multifocal motor neuropathy – IgM anti-GM1 ganglioside antibodies – Conduction blocks in lower motor neurons  Neuromyelitis optica (Devic’s syndrome) – Autoimmune attack against optic nerves and spinal cord  Dermatomyositis – Microangiopathy in perifascicular regions of muscles and skin aIn addition to atypical haemolytic uraemic syndrome, dense deposit disease, paroxysmal nocturnal haemoglobinuria, age-related macular degeneration and hereditary angio-oedema; AChR, acetylcholine receptor
  21. 21. Dysregulation of complement activation: STEC-HUS, atypical HUS and TTP Marina Noris, Federica Mescia and Giuseppe Remuzzi Nat Rev Nephrol, 2012
  22. 22. Eculisumab The only drug of complementinhibiting antibodies for the treatment of atypical HUS, PNG
  23. 23. Approaches to target complement inhibitors to various surfaces either in circulation or after ex vivo coating/perfusion Ricklin and Lambris 2007 ; Monk et al. 2007; Qu et al. 2009 ; Woodruff et al. 2011 ; Recknagel et al. 2012; Schmidt et al. 2012; D. Ricklin and J.D. Lambris 2012
  24. 24. Overview of complement-modulating agents under development Ingibitor name Mechanism of action Stage of development (Company) FCFD4514S (Genentech) CR2-fH (TT30) (Taligen Therapeutics/Alexion) PMX53 (Promcs/Cephalon) CCX168 (ChemoCentryx) Mubodina (ADIENNE) Monoclonal antibody Fab fragment against factor D Fusion protein linking CFH regulatory domain to the part of complement receptor CR2 that binds C3b, thereby delivering CFH to sites of complement activation C5a receptor antagonist C5a receptor antagonist Recombinant human minibody against C5 Phase Ib/II in AMD Phase I in PNH Phase Ib/IIa in RA Phase II in ANCA-associated renal vasculitis Preclinical NNC 0151-0000-0000 (Novo Nordics) Anti-C5a receptor antibody Phase I in SLE Phase II in RA Recombinant CFH (Taligen Therapeutics/Optherion) Restores/potentiates the action of endogenous CFH Preclinical CFH from human plasma (LFB) Restores/potentiates the action of endogenous CFH Preclinical Marina Noris, Federica Mescia and Giuseppe Remuzzi Nat Rev Nephrol, 2012
  25. 25. Examples of complement-related disorders with different potential requirements concerning drug administration
  26. 26. Conclusion  Activation of complement in many diseases is a normal physiological response  There are very few diseases in which complement is not activated  Complement activation can be pathogenic when it is dysregulated and persistent  There is little rationale for complement inhibition in situations where activation is part of the process of disease resolution  Complement must be constantly monitored, as it is always active and has a destructive force
  27. 27. Q&A