Complement Cascade Review

Flashcards covering the initiation, activation, amplification, and membrane attack phases of the complement cascade, including key components, regulatory mechanisms, and clinical relevance for transfusion scientists.

What is the primary role of the complement system?

It is part of our innate immune defense mechanism, tackling infection by causing cell lysis or flagging pathogens for phagocytosis.

Why is complement activation in transfusion considered an "unintended consequence"?

Because transfusion of allogeneic red cells is an artificial circumstance, and complement activation by red cell antibodies is not its primary intended role.

What conditions are required for IgG antibodies to initiate the classical complement cascade?

At least two IgG antibodies must bind to their target antigens in very close proximity, providing two available Fc components for C1 binding, and calcium ions are required.

Why is a single IgM antibody more effective at initiating complement than a single IgG antibody?

A single IgM molecule has five available Fc portions, making it extremely capable of C1 binding regardless of antigen spatial arrangement, whereas IgG requires two Fc components in close proximity.

What is the sequential order of complement protein activation in the classical pathway?

C1, C4, C2, C3, C5, C6, C7, C8, C9.

Which component of C1 binds to the Fc portions of antibodies?

C1q.

What does activated C1QRS cleave, and into what components?

It cleaves C4 into C4B and C4A, and C2 into C2B and C2A.

Which complement components form the C3 convertase in the classical pathway?

C4b and C2b.

What is the function of C3 convertase, and what are its cleavage products from C3?

C3 convertase cleaves C3 into C3b and C3a. C3a is an anaphylatoxin and C3b can bind to the C4b2b complex or the red cell surface.

Why is the cleavage of C3 into C3b and C3a by C3 convertase called the "amplification stage"?

A single C4b2b complex (C3 convertase) is capable of cleaving hundreds of C3 proteins, greatly increasing the complement response.

Which complement components form the C5 convertase in the classical pathway?

C4b2b3b.

What does C5 convertase cleave, and what are the roles of the cleavage products?

C5 convertase cleaves C5 into C5b and C5a. C5a is a powerful anaphylatoxin and pro-inflammatory mediator, and C5b initiates the formation of the Membrane Attack Complex (MAC).

What is the sequence of complement proteins that form the Membrane Attack Complex (MAC) after C5b binds to the cell membrane?

C5b attracts C6, which attracts C7, which attracts C8, which then attracts multiple C9 proteins to form a pore-like structure.

How does the Membrane Attack Complex (MAC) cause cell lysis?

The MAC creates a pore-like hole in the cell membrane, allowing uncontrolled passage of water and sodium ions into the cell, causing it to swell uncontrollably and burst.

Explain the phenomenon of "innocent bystander hemolysis" in the context of complement activation during a transfusion reaction.

Once the membrane attack stage is activated, the C5b component can bind to any red cell in the vicinity, including the patient's own antigen-negative red cells, causing their lysis alongside the incompatible transfused cells.

How does C1 inhibitor regulate the complement cascade?

C1 inhibitor binds to the C1 antibody-antigen complex, inactivating C1 and halting the cascade, preventing any release of anaphylatoxins.

How can the lability of C2b affect the complement cascade?

If C2b degrades before the C4b2b (C3 convertase) complex can bind to the red cell, the cascade is halted during the activation stage.

What happens to C3b components, and what is their end product that is detectable in laboratory tests?

C3b components are labile and quickly inactivate, degrading to IC3b, which then further degrades into C3dg, an inert membrane-bound structure detectable as C3 or C3d.

What does a positive reaction for C3d using polyspecific AHG indicate?

It indicates that a person's complement cascade has been initiated at some point, providing evidence of in vivo complement activation.

Name two membrane-bound proteins that inhibit the membrane attack phase of the complement cascade.

C8 binding protein and CD59 (Protectin/Membrane Inhibitor of Reactive Lysis).

How does CD59 inhibit the membrane attack complex formation?

CD59 inserts itself into the C5b678 complex, preventing the addition of C9, and can also bind to membrane-bound C9 molecules, disrupting the formation of the C9 pore complex.

What condition is associated with a lack of CD59, and what is its cause?

Paroxysmal Nocturnal Hemoglobinuria (PNH), which is an inherited defect of the red cell membrane itself, not associated with blood group antibodies.