Anastasios E. Germenis
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1 Anastasios E. Germenis Professor and Chairman Department of Immunology & Histocompatibility School of Medicine University of Thessaly University Hospital of Larissa Greece
2 The Complement System A major system of innate immunity and one of the main effector mechanisms of antibody-mediated immunity
3 The Complement System A. Complement components Inert soluble proteins that upon activation exert enzymatic activity whose the substrate is the next protein of the cascade B. Complement receptors Ligands of the CRs are the cleavage products and/or the protein complexes produced during complement activation C. Regulatory proteins (soluble and membrane-associated) Along with a series of physicochemical regulatory mechanisms, aim to: focus the complement activation on the surface of invading pathogens limit the deposition of complement on normal/homologous cells and tissues
4 Lectin pathway Classical pathway Activators: Immune complexes or immune aggregates containing IgM > IgG3 > IgG1 > IgG2 > IgG4 Gram(+), Gram( ) bacteria, viruses Cellular and subcellular structures from damaged cells (several proteins, lipids, etc.) Other compounds (e.g. sodium urate crystals) CRP MBL recognizes arrays of conserved oligosaccharides shared by broad classes of microorganisms
5 The similar structure of complement activation molecules C1q of the classical pathway, MBL of the lectin pathway and L-ficolin
6 Characteristics of ficolins
7 Alternative pathway and amplification loop The carbohydrate environment of the surface on which the C3b is deposited determines the relative affinity of C3b to factor H or B: Host cell surfaces rich in polyanions affinity to factor H Microbial surfaces poor in polyanions affinity to factor B
8 The three complement pathways converge at the point of cleavage of C3
9 The terminal pathway
10 Established pathways of C activation associated with the new activation pathway and crosstalk between cells and the coagulation cascade with C
11 Regulation of the complement
12 The Main Physiologic Activities of the Complement System A. Host defense against infection 1. Chemotaxis and leukocyte activation Neutrophils: Activation Adhesion to endothelium Emigration Chemotaxis Mast cells: Degranulation Monocytes: Activation with release of IL-1 & IL-6
13 The Main Physiologic Activities of the Complement System A. Host defense against infection 2. Opsonization C3b
14 The Main Physiologic Activities of the Complement System B. Interface between innate and adaptive immunity 1. Augmentation of antibody responses 2. Enhancement of immunologic memory
15 The Main Physiologic Activities of the Complement System C. Diposal of waste 1. Clearance of immune complexes Antigens RBC Immune complex binding to RBC via complement and CRs
16 The Main Physiologic Activities of the Complement System C. Diposal of waste 1. Clearance of immune complexes Kupffer cells and spleen Mφ RBC RBC transports immune complex to spleen & liver where the complexes are removed by phagocytes
17 The Main Physiologic Activities of the Complement System C. Diposal of waste 2. Clearance of apoptotic cells
18 Complement activates cells involved in both the adaptive and innate immune response
19 Mastellos D, Lambris JD. Trends Immunol 2002;23:485 Role of C3 in osteoclast differentiation during bone development
20 Mastellos D, Lambris JD. Trends Immunol 2002;23:485 Effects of complement in hematopoietic development
21 Contribution of complement to liver regeneration Mastellos D, Lambris JD. Trends Immunol 2002;23:485
22 Complement system sensing of exogenous and endogenous danger in the fluid phase
23 Complement regulation of TLR-induced cytokines of the IL-12 family
24 Estimated prevalence : 0.03% Deficiency C1-INH deficiency 1 case per 50,000 persons Prevalence MBL deficiency low protein levels: 35% lack of functional protein: 5% of the Caucasian population MASP-2 deficiency C2 deficiency C6 deficiency C9 deficiency 15 per 100,000 persons in Sweden 5 per 100,000 persons in Western countries 1:1,600 among African Americans 0.1% in Japan population
25 Inherited complement deficiencies Tedesco F. Vaccine 2008;265:13 8
26 Tedesco F. Vaccine 2008;265:13 8 Bacterial infections Deficient components Strains of bacteria Frequency % C1, C4, C2 Neisseria S. pneumoniae H. influenzae S. aureus C3, H, I Neisseria S. pneumoniae H. influenzae S. aureus C5, C6, C7, C8 Neisseria S. pneumoniae H. influenzae S. aureus
27 Prevalence of complement deficiency in meningococcal disease (%) Neisserial infections and inherited complement deficiencies Japan Figueroa JE, Densen P, 1991 x250 risk Iowa New York Colorando Israel S. Africa Denmark x risk Incidence of meningococcal disease (cases/10 6 population) The prevalence of complement deficiencies in individuals with systemic meningococcal infections In recurrent disease 40% In cases with positive family history of meningococcal disease 10% In patients with an unusual serotype 20 50% In sporadic cases 1 15% Tedesco F. Vaccine 2008;265:13 8
28 Meningococcal disease Parameter Normal LCCD Properdin deficient No of homozygotes No with meningococcal disease Frequency of infection (%) Male/female ratio 1.3:1 2.2:1 21:0 37:1 Median age (yr), first episode Recurrence rate (%) Relapse rate (%) Mortality/100 episodes (%) Infecting serogroup No of isolates 3, % B % Y Figueroa JE, Densen P. Clin Microbiol Rev 1991;4:359 95
29 Inherited complement deficiencies Tedesco F. Vaccine 2008;265:13 8 Pickering MC et al. Adv Immunol 2000;76:
30 SLE in complement deficiencies Low (or absent) titers of ANA and/or anti-dna antibodies Higher incidence of anti-ro antibodies Severity variable C1 deficiency early onset CNS disease very severe most common cause of death is infection C2 deficiency milder phenotype prominent annular photosensitive dermatitis renal disease infrequent C4 deficiency early onset very severe high mortality rate
31 Dysregulation of the alternative complement pathway
32 Dysregulation of the alternative complement pathway ahus AMD DDD DDD (and PLD) ahus AMD CFH mutations and partial deficiency CFH total deficiency MCP mutations C3 polymorphisms CFB gain-of-function mutations CFI heterozygous deficiency SERPNG1 polymorphisms Nef Anti-CFH autoantibodies Anti-CFB autoantibodies
33 Screening for complement deficiencies SEELEN MA, ROOS A,WIESLANDER J, MOLLNES TE, SJÖHOLM AG, WURZNER R,LOOS M, TEDESCO F, SIM RB, GARRED P, ALEXOPOULOS E, TURNER MW, DAHA MR Functional analysis of the classical, alternative, and MBL pathways of the complement system: standardization and validation of a simple ELISA J Immunol Methods 2005;296(1-2):187-98
34 Examples of pathological conditions involving the complement system
35 Regulation, deactivation and inhibition of the complement cascade on host cells by natural regulators and complement-specific therapeutics
36 Complement therapeutics on the market or in clinical trials
37 Complement therapeutics in pre-clinical development
38 Ever since its discovery, complement has continued to interest and puzzle investigators Louis Pillemer, 1943
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