- Complement System:
- The complement cascade is a system of immune proteins:
- That activates in a cascade-like fashion:
- To fight infection and promote tissue repair:
- But also contributes to inflammation and disease when overactivated
- To fight infection and promote tissue repair:
- That activates in a cascade-like fashion:
- It works via three pathways (classic, lectin, alternative):
- That converge to create inflammatory fragments called:
- Anaphylatoxins and form a membrane attack complex (MAC) that can kill pathogens
- That converge to create inflammatory fragments called:
- Beyond infection:
- Complement plays roles in clearing cellular debris, facilitating tissue regeneration, and regulating neuronal function:
- But inappropriate activation can cause:
- Chronic pain, autoimmune disease, and organ damage
- But inappropriate activation can cause:
- Complement plays roles in clearing cellular debris, facilitating tissue regeneration, and regulating neuronal function:
- Pathways and Triggers:
- Each pathway initiates the cascade through different triggers but ultimately leads to the same outcomes:
- Classical Pathway:
- Activated by the binding of antibodies (like IgG and IgM) to antigens:
- On the surface of a pathogen
- Activated by the binding of antibodies (like IgG and IgM) to antigens:
- Lectin Pathway:
- Initiated when mannose-binding lectin (MBL):
- Binds to carbohydrate structures on bacterial cell walls
- Initiated when mannose-binding lectin (MBL):
- Alternative Pathway:
- Triggered by the direct binding of complement components to foreign surfaces, such as pathogens, without the need for antibodies
- Classical Pathway:
- Classical pathway (antibody-dependent):
- Trigger:
- C1q, a component of the C1 protein complex:
- Binds to an antibody-antigen complex:
- On a pathogen surface
- The C1 complex is composed of:
- C1q, C1r, and C1s
- Binds to an antibody-antigen complex:
- C1q, a component of the C1 protein complex:
- Cascade:
- C1r and C1s are activated:
- Which then cleave complement proteins C4 and C2
- The larger fragments, C4b and C2b (also called C2a):
- Bind together to form the classical pathway’s C3 convertase (C4b2b)
- C1r and C1s are activated:
- Antigen – antibody complexes:
- Best:
- IgM:
- Then IgG1 / IgG3
- IgM:
- Best:
- Early components unique to this pathway:
- C1 (C1q, C1r, C1s), C2, C4
- C1 protein complex:
- Needs Ca²⁺:
- To stay assembled
- Needs Ca²⁺:
- Trigger:
- Lectin pathway (antibody-independent; same cascade as classical after C4):
- Trigger:
- The pattern recognition molecule:
- Mannose-binding lectin (MBL) or ficolins:
- Bind to specific carbohydrate patterns (like mannose) on the surface of pathogens
- Mannose-binding lectin (MBL) or ficolins:
- The pattern recognition molecule:
- Cascade:
- This binding activates MBL-associated serine proteases (MASPs):
- Which are functionally similar to C1r and C1s
- The MASPs cleave C4 and C2:
- Forming the same C3 convertase (C4b2b) used by the classical pathway
- This binding activates MBL-associated serine proteases (MASPs):
- Mannose-binding lectin (MBL) or ficolins binding microbial sugars:
- Enzymes:
- MASP-1 / MASP-2 cleave C4 and C2:
- Merges with classic pathway a:
- C3 convertase (C4b2a)
- Merges with classic pathway a:
- MASP-1 / MASP-2 cleave C4 and C2:
- Enzymes:
- Trigger:
- Alternative pathway (antibody-independent; tickover on surfaces):
- Trigger:
- This pathway is always active at a low level through a “tickover” mechanism:
- Where C3 is spontaneously hydrolyzed
- It is further activated when C3b, a fragment of C3:
- Binds directly to the surface of a pathogen or foreign material
- This pathway is always active at a low level through a “tickover” mechanism:
- Cascade:
- Factor B binds to the surface-bound C3b and is then cleaved by Factor D to form C3bBb:
- The alternative pathway’s C3 convertase
- The protein properdin stabilizes this complex:
- Amplifying the cascade
- This pathway also acts as an amplification loop for the classical and lectin pathways
- Factor B binds to the surface-bound C3b and is then cleaved by Factor D to form C3bBb:
- Spontaneous C3 hydrolysis on microbial / endotoxin surfaces:
- Amplified by Factor B, Factor D, Properdin (P)
- Note:
- Mg²⁺ is required for Factor B binding to C3b
- Properdin stabilizes the convertase
- Common note:
- C3:
- Common to and is the convergence point for the three pathways
- C3:
- Trigger:
- The final, common pathway:
- All three initiation pathways converge to form a C3 convertase:
- Which ultimately leads to the creation of the:
- Membrane attack complex (MAC)
- Which ultimately leads to the creation of the:
- C3 cleavage:
- A C3 convertase cleaves C3 into two pieces:
- C3a:
- A small fragment that acts as a potent:
- Anaphylatoxin, triggering inflammation
- A small fragment that acts as a potent:
- C3b:
- A larger fragment that acts as an opsonin, or “tag,” marking the pathogen for destruction
- It also attaches to the C3 convertase to create a C5 convertase
- C3a:
- A C3 convertase cleaves C3 into two pieces:
- C5 cleavage:
- The C5 convertase cleaves C5 into C5a (a potent anaphylatoxin and chemoattractant) and C5b
- Membrane Attack Complex (MAC):
- The C5b fragment recruits and assembles the remaining complement proteins (C6, C7, C8, and multiple C9 molecules):
- To form a cylindrical pore in the pathogen’s membrane:
- This pore disrupts the cell’s osmotic balance:
- Causing it to lyse and die
- This pore disrupts the cell’s osmotic balance:
- To form a cylindrical pore in the pathogen’s membrane:
- The C5b fragment recruits and assembles the remaining complement proteins (C6, C7, C8, and multiple C9 molecules):
- All three initiation pathways converge to form a C3 convertase:
- C3 / C5 Convertases (know these cold):
- Classical / Lectin pathway:
- C3 convertase:
- C4b2a
- C5 convertase:
- C4b2a3b
- C3 convertase:
- Alternative pathway:
- C3 convertase:
- C3bBb:
- Stabilized by Properdin / P
- C3bBb:
- C5 convertase:
- C3bBb3b
- C3 convertase:
- Effector Functions (the “what does each piece do?”):
- Anaphylatoxins:
- C3a, C4a, C5a:
- ↑ vascular permeability
- Vasodilation
- Bronchoconstriction
- Mast cell / basophil degranulation
- Potency:
- C5a > C3a >> C4a (C4a is weak)
- C3a, C4a, C5a:
- Chemotaxis (especially neutrophils):
- C5a is the major chemoattractant:
- C3a contributes mainly as anaphylatoxin
- C5a drives:
- Leukocyte recruitment
- Adhesion up-regulation
- Oxidative burst
- C5a is the major chemoattractant:
- Opsonization:
- C3b (and iC3b), C4b
- Coat pathogens (marks them for destruction):
- CR1 / CR3 on phagocytes bind → enhanced phagocytosis
- Membrane Attack Complex (MAC):
- C5b to C9
- C5b:
- Nucleates assembly with C6, C7, C8, C9 (polymerizes) → pore → osmotic lysis (classically Neisseria)
- Anaphylatoxins:
- Ion Requirements (exam-friendly correction):
- Classical and Lectin Pathway:
- Ca²⁺ required for C1qrs (classical) and MBL – MASP (lectin) complexes:
- Mg²⁺ also involved downstream
- Ca²⁺ required for C1qrs (classical) and MBL – MASP (lectin) complexes:
- Alternative pathway:
- Mg²⁺ essential for Factor B – C3b interaction and convertase formation:
- So: not “Mg for both pathways”:
- Only – Classical / Lectin need Ca²⁺
- Alternative needs Mg²⁺ (and Properdin)
- So: not “Mg for both pathways”:
- Mg²⁺ essential for Factor B – C3b interaction and convertase formation:
- Classical and Lectin Pathway:
- Regulation (why we don’t self-destruct):
- C1 inhibitor (C1-INH):
- Blocks C1r / C1s and MASPs 1/2 (MASP-1 / MASP-2 cleave C4 and C2):
- Turns off classic / lectin pathways early
- Blocks C1r / C1s and MASPs 1/2 (MASP-1 / MASP-2 cleave C4 and C2):
- Factor H and Factor I:
- Inactivate C3b (→ iC3b) on host cells:
- Factor H prefers sialic acid – rich self surfaces
- Inactivate C3b (→ iC3b) on host cells:
- DAF / CD55:
- Disrupts C3 / C5 convertases on host cells
- CD59 (Protectin):
- Blocks C9 polymerization:
- Prevents MAC on self cells
- Blocks C9 polymerization:
- Clinical Correlates (high-yield):
- C1-INH deficiency → Hereditary angioedema:
- Bradykinin-mediated edema:
- ACE inhibitors worsen
- Treat with C1-INH concentrate, bradykinin pathway blockers
- Bradykinin-mediated edema:
- C2 deficiency (most common classic pathway deficiency):
- SLE-like disease, recurrent sinopulmonary infections
- C3 deficiency:
- Recurrent severe pyogenic infections:
- Especially encapsulated bacteria; immune complex disease.
- Recurrent severe pyogenic infections:
- Terminal complement (C5 to C9) deficiency:
- Recurrent Neisseria (meningitidis, gonorrhoeae)
- DAF / CD55 or CD59 deficiency (e.g., PNH via PIGA mutation):
- Intravascular hemolysis, hemoglobinuria, thrombosis
- Treat with C5 inhibitors:
- Eculizumab / ravulizumab
- Factor H / I abnormalities:
- Atypical HUS, C3 glomerulopathy
- C1-INH deficiency → Hereditary angioedema:
- Laboratory Assessment:
- CH50:
- Total classic pathway function:
- Low in classic component defects or terminal pathway defects
- Total classic pathway function:
- AH50:
- Total alternative pathway function
- Heat-labile:
- Complement activity falls if serum is mishandled / warmed
- CH50:
- C1 inhibitor (C1-INH):
- Quick “Apply It” Pearls:
- Suspected meningococcemia with recurrence:
- Check terminal complement (C5 to C9)
- Recurrent pyogenic infections with low C3:
- Evaluate classic / alternative convertase regulation
- Episodic angioedema without urticaria:
- Think C1-INH deficiency
- Autoimmunity in a young patient + low early classic components (C1q/C2/C4) → screen for complement deficiencies
- Suspected meningococcemia with recurrence:
- One-Page Memory Map:
- Triggers:
- Classic pathway:
- IgM / IgG immune complexes → C1qrs (Ca²⁺)
- Lectin pathway:
- MBL / ficolin (MASPs) → C4, C2
- Alternative pathway:
- C3 tackover + B, D, Properdin (Mg²⁺)
- Convertases:
- Classic / Lectin:
- C4b2a (C3), C4b2a3b (C5)
- Alternative:
- C3bBb (C3), C3bBb3b (C5)
- Classic / Lectin:
- Effectors:
- Opsonins:
- C3b/iC3b (± C4b)
- Anaphylatoxins:
- C5a > C3a >> C4a
- Chemotaxis:
- C5a
- MAC: C5b to C9
- Opsonins:
- Regulators:
- C1-INH, Factor H / I, DAF (CD55), CD59
- Deficiencies (buzzwords):
- C1-INH—HAE
- C2—SLE-like
- C3—pyogenic infections
- C5–C9—Neisseria
- DAF/CD59—PNH
- Factor H/I—aHUS
- Classic pathway:
- Triggers:
- Classical / Lectin pathway:
- Each pathway initiates the cascade through different triggers but ultimately leads to the same outcomes:
- The complement cascade is a system of immune proteins:
Rodrigo Arrangoiz MS, MD, FACS, FSSO 