Fig. 1: The complement cascade.

The complement cascade is a major mechanism for host cells to mount an effective immune response against invading pathogens and is activated by three independent pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP). Activation of the CP, by pathogen or antibody binding (1), or the LP, by the binding of pattern-recognition molecules to pathogen-associated molecular patterns (2), results in the cleavage of C4 to C4a and C4b and C2 to C2a (smaller activation fragment) and C2b (larger fragment containing the serine protease domain)⁴⁴ via the C1s protease or MBL-associated serine proteases, respectively (3). C4b and C2b join to form an active C3 convertase. Activation of the AP by pathogens and injured tissue causes low-grade hydrolysis of C3, with the resultant C3b binding to FB (4). Cleavage of FB by FD produces the alternative C3 convertase (C3bBb), at which point the three pathways merge (5). The C3 convertases cleave C3 into C3a and C3b. C3a binds the C3a receptor (C3aR) to induce inflammation (6), while C3b joins the C3 convertases to create the C5 convertases (C4b2a3b and C3bBbC3b) (7). The C5 convertases cleave C5 to C5a and C5b, which lead to inflammation via the C5a receptor, and cell lysis and death via MACs in the cell membrane formed from C5b, C6, C7, C8, and C9 (8). C2 participates in both the CP and LP, making it a target for intervention therapy for disorders affecting these pathways. Binding of empasiprubart to C2 (9) prevents formation of the C4bC2 complex upstream of C3 and the subsequent activation of the CP and LP, while leaving the AP intact. Parts of this figure were adapted from Burgelman M, Dujardin P, Vandendriessche C, and Vandenbroucke RE (2023). Free complement and complement-containing extracellular vesicles as potential biomarkers for neuroinflammatory and neurodegenerative disorders. Front. Immunol. 13:1055050. doi: 10.3389/fimmu.2022.1055050 licensed under CC BY 4.0. Ab antibody, Ag antigen, C complement factor, C3aR C3a receptor, C5aR C5a receptor, FB factor B, FD factor D, MAC membrane attack complex, MBL-MASP mannose-binding lectin–associated serine protease.