immuno 4: complement

What is the complement system?

A rapid signaling cascade of ~20–30 proteins in serum and on cell surfaces that destroys pathogens and recruits immune responses; part of both innate and adaptive immunity.

What are the main goals of complement? (Mnemonic)

Destroy!!!

“OLD” = Opsonization, Lysis, Defense (inflammation/recruitment)

• Opsonize pathogens

• Lyse cells

• Recruit immune cells

How are complement proteins named and activated?

Named C1–C9; most are inactive zymogens activated by cleavage in a cascade.

What happens when complement proteins are cleaved? (Mnemonic)

: “a = Away, b = Binds”

• “a” = anaphylatoxins. small, soluble (inflammation)

• “b” = large, binds pathogen
  ⚠ Exception: C2 (reversed)

What are the 3 complement pathways?

• Classical (antibody)

• Alternative (pathogen surface)

• Lectin (mannose binding – not emphasized here)

What is shared between all complement pathways?

Same C3 activation → same terminal pathway → same functions (MAC, opsonization, inflammation)

What is opsonization in complement?

C3b and C4b coat pathogens → act as “eat me” signals → increase phagocytosis via complement receptors.

Which complement proteins act as opsonins?

C3b (most important) and C4b

What is the MAC and its function? (Mnemonic)

MAC = “Makes A hole in Cell”
C5b6789 forms pores → lyses membrane pathogens (Gram– bacteria, enveloped viruses).

What are anaphylatoxins and their function? (Mnemonic)

“C3a, C4a, C5a = A for Anaphylaxis”

• Increase vascular permeability on vascular endothelial cells

• Recruit neutrophils

• Promote inflammation

What activates the classical pathway?

Antigen-antibody complexes (IgG or IgM).

Is the classical pathway innate or adaptive?

Adaptive-triggered (requires antibodies), but part of complement effector system.

What is required to activate C1?

Binding to 2 Fc regions of antibodies attached to antigen.

What is the classical pathway sequence? (Mnemonic)

“1-4-2-3-5-9” (weird order!)
C1 → C4 → C2 → C3 → C5–9

What happens after C1 activation?

• Cleaves C4 → C4b binds pathogen

• Cleaves C2 → C2a binds C4b > C4b2a

What does C4b2a C3 convertase do?

Cleaves C3 →

• C3a (inflammation)

• C3b (binds, opsonin, amplifies cascade)

What is the C5 convertase in the classical pathway?

C4b2a3b

What does C5 convertase do?

Cleaves C5 →

• C5a (strong anaphylatoxin)

• C5b (starts MAC formation)

How is the MAC formed?

C5b + C6 + C7 + C8 + multiple C9 → pore formation

What is the key endpoint of the classical pathway?

Pathogen death via MAC, opsonization, and inflammation

What activates the alternative pathway?

Pathogen surfaces (LPS, microbes, viruses) — no antibodies needed

Why is C3 important in the alternative pathway?

C3 is spontaneously cleaved → provides constant low-level activation.

What happens to free C3b if no pathogen is present?

It is rapidly inactivated (prevents damage to host cells).

What is the alternative pathway sequence? (Mnemonic)

“C3 → B → D → Properdin → C3 → C5–9”
Think: “3 Becomes Dangerous Properly”

Steps of alternative pathway activation?

• C3 → C3b binds pathogen

• Factor B binds → C3bB

• Factor D cleaves → C3bBb (C3 Convertaase)

• Properdin stabilizes

What is the C3 convertase in the alternative pathway?

C3bBb

What is the C5 convertase in the alternative pathway?

C3bBb3b

Final outcome of alternative pathway?

Same as classical → MAC formation (C5b6789)

Why must complement be regulated?

To prevent damage to host cells from uncontrolled activation.

What inhibits the classical pathway?

C1 inhibitor (C1INH) → blocks C4 and C2 cleavage.

How is C3 activity regulated?

Factor H + Factor I → inactivate C3b.

How is MAC formation inhibited?

Protectin (CD59) → prevents C9 recruitment.

What is the most important central component of complement?

C3 — all pathways converge here.

What are the 3 major outcomes after C3 activation?

• C3b → opsonization

• C3a → inflammation

• C5b → MAC

Which complement fragment is the strongest chemoattractant?

C5a

Which pathogens are most susceptible to MAC?

Gram-negative bacteria + enveloped viruses

What cells respond to complement opsonization?

Macrophages and neutrophils via complement receptors.

Key difference: classical vs alternative pathway?

• Classical = antibody-dependent

• Alternative = antibody-independent (innate)

Ultimate purpose of complement system?

Rapidly tag, recruit, and destroy pathogens through coordinated immune amplification.