Alternative pathway is constitutively active via
spontaneous C3 "tick-over" hydrolysis in plasma. C3(H₂O) + Factor B
+ Factor D → C3bBb convertase → Properdin (P) stabilises →
amplification loop.
Lectin pathway is triggered by Mannose-Binding
Lectin (MBL) recognising carbohydrate patterns on pathogens →
MASP-1/MASP-2 activate → cleave C4 and C2 (same as classical from
here).
Opsonization: C3b covalently binds pathogen
surface, flagging it for phagocytosis by macrophages/neutrophils via
CR1 receptors.
MAC (Membrane Attack Complex): C5b+C6+C7+C8+(C9)ₙ
form a transmembrane pore → ion gradient collapses → lysis of
Gram-negative bacteria.
The complement system is a set of roughly 50 plasma and cell-surface proteins that form the first biochemical line of defence of innate immunity. When activated, these proteins undergo a tightly regulated proteolytic cascade — a chain reaction in which each cleavage event amplifies the next — ultimately tagging pathogens for destruction by phagocytes (opsonisation via C3b), triggering inflammation through anaphylatoxins (C3a, C5a), and punching lethal pores through bacterial membranes via the Membrane Attack Complex (MAC, C5b-9). Three distinct pathways — classical, lectin, and alternative — converge on a common terminal sequence.
This simulation animates C3 and initiator proteins diffusing through plasma before binding to the pathogen surface. Adjust C3 concentration, initiator abundance, complement inhibitors (DAF/CD55), and temperature using the sliders; toggle between the classical, alternative, and lectin pathways to see how each reaches the same lytic endpoint. Watch C3b deposits accumulate, convertases become active, and MAC pores lyse the bacterium as the green cell transitions to red.
Frequently Asked Questions
What triggers the classical complement pathway?
The classical pathway is initiated when C1q — a hexameric recognition protein with a bouquet-like structure — binds to the Fc regions of IgG or IgM antibodies already attached to a pathogen surface. This activates C1r and C1s serine proteases, which cleave C4 into C4a and C4b, and C2 into C2a and C2b, assembling the C3 convertase C4b2a. A single antigen–antibody complex can activate dozens of C3 molecules, illustrating the amplification power of the cascade.
How does the alternative pathway differ from the classical pathway?
The alternative pathway requires no antibodies. Instead, it exploits the spontaneous, low-level hydrolysis of C3 in plasma ("tick-over") to generate C3(H₂O), which binds Factor B; Factor D then cleaves Factor B to form the fluid-phase convertase C3(H₂O)Bb. On pathogen surfaces — which lack the regulatory proteins present on host cells — C3b deposits recruit more Factor B and D to form the surface-bound convertase C3bBb, stabilised by Properdin. This creates a self-amplifying loop that can account for 80–90% of total C3b deposition.
What is the Membrane Attack Complex and how does it lyse bacteria?
The MAC (C5b-6-7-8-9) is a transmembrane pore approximately 10 nm in diameter. After C5 convertase cleaves C5 into C5a and C5b, C5b sequentially recruits C6, C7, and C8, which insert into the lipid bilayer. Multiple C9 molecules then polymerise around this seed to form the final pore, which disrupts the ion gradients that maintain osmotic balance, causing water influx, swelling, and lysis. MAC is effective primarily against Gram-negative bacteria; Gram-positive bacteria are protected by their thick peptidoglycan wall.
What is opsonisation and why is it important?
Opsonisation is the coating of a pathogen with complement proteins (primarily C3b) or antibodies to enhance phagocytosis. C3b covalently binds to the pathogen surface via an internal thioester bond that reacts with hydroxyl or amino groups — a process lasting only microseconds. Macrophages and neutrophils carry complement receptor 1 (CR1, CD35) that recognises C3b, dramatically increasing the rate of phagocytic engulfment. Without opsonisation, many encapsulated bacteria such as Streptococcus pneumoniae can evade phagocytosis entirely.
What do C3a and C5a do as anaphylatoxins?
C3a and C5a are small soluble fragments released during C3 and C5 cleavage that act as anaphylatoxins — potent mediators of inflammation. C5a is roughly 100-fold more potent than C3a. They bind G-protein-coupled receptors (C3aR and C5aR/CD88) on mast cells, basophils, and neutrophils, triggering histamine release, increased vascular permeability, and chemotaxis of inflammatory cells to the infection site. Excessive C5a signalling is implicated in the cytokine storm of severe COVID-19 and sepsis.
How do regulatory proteins prevent complement attacking host cells?
Host cells express several surface proteins that inactivate complement. Decay-accelerating factor (DAF/CD55) accelerates the spontaneous dissociation of C3 and C5 convertases, preventing further C3b deposition. CD59 (protectin) blocks C9 polymerisation, preventing MAC formation. Factor I cleaves fluid-phase C3b into inactive iC3b with the help of Factor H. These mechanisms collectively ensure complement attacks pathogens but spares "self" tissue — a failure mode illustrated by Paroxysmal Nocturnal Haemoglobinuria (PNH), where loss of GPI-anchored proteins (including CD55/CD59) leads to red blood cell destruction.
What is Paroxysmal Nocturnal Haemoglobinuria (PNH)?
PNH is a rare acquired disorder caused by a somatic mutation in the PIG-A gene of a haematopoietic stem cell, abolishing GPI-anchor synthesis. The resulting blood cells lack CD55 and CD59, making them vulnerable to complement lysis — particularly at night when respiratory acidosis slightly lowers pH and activates complement. Patients suffer haemolytic anaemia, thrombosis, and dark urine. The anti-C5 monoclonal antibody eculizumab (Soliris) revolutionised treatment by blocking MAC formation, demonstrating the therapeutic importance of understanding complement regulation.
How does temperature affect the cascade speed in this simulation?
Complement enzymes, like all biological catalysts, follow Arrhenius kinetics: reaction rates roughly double for every 10 °C rise (Q₁₀ ≈ 2). The simulator models this with an Arrhenius-like factor exp[0.05×(T−37)], so raising temperature from 37 °C to 42 °C increases the effective rate by ~28%, whilst cooling to 20 °C reduces it by ~65%. Therapeutic hypothermia used during cardiac surgery deliberately slows complement activation to limit ischaemia-reperfusion injury to transplanted organs.
What role does the lectin pathway play in innate immunity?
The lectin pathway is activated by Mannose-Binding Lectin (MBL) or Ficolins recognising conserved carbohydrate patterns (mannose, N-acetylglucosamine) on pathogen surfaces — patterns largely absent from mammalian cell surfaces. MBL forms complexes with MASP-1 and MASP-2 serine proteases that cleave C4 and C2 (exactly as in the classical pathway from this point onward). MBL deficiency is one of the most common human immunodeficiency states, predisposing children to recurrent respiratory infections during the period before adaptive immunity matures.
Are there therapeutic complement inhibitors?
Yes — complement therapeutics have become a major drug class. Eculizumab (anti-C5) treats PNH, atypical haemolytic uraemic syndrome (aHUS), and neuromyelitis optica. Ravulizumab is a long-acting anti-C5 antibody requiring only 8-weekly dosing. C3 inhibitors such as pegcetacoplan are approved for PNH and target the amplification loop. The simulator's "inhibitor" slider represents DAF/CD55-like regulatory activity — raising it blocks convertase assembly, reducing C3b deposition and MAC pore formation proportionally.
How does complement interact with the adaptive immune system?
Complement bridges innate and adaptive immunity. C3b-coated antigens are captured by dendritic cells via CR3, enhancing antigen presentation and lowering the B-cell activation threshold roughly 1,000-fold. C3d fragments on antigens engage the B-cell co-receptor CD21, amplifying B-cell signalling. Complement deficiencies — particularly of C1q, C4, or C2 — are strongly associated with systemic lupus erythematosus (SLE), because impaired clearance of apoptotic cell debris allows nuclear antigens to escape and drive autoimmunity.