Complement

Think of complement as a rapid-response security system in your plasma. It’s a cascade of proteins that, once triggered, amplifies quickly to neutralize threats. While it’s part of the innate system, it works closely with antibodies (adaptive system) and has major implications in blood banking

Complement activation starts via antibody binding (Classical) or spontaneously (Alternative), converges at the C3/C5 convertase steps, and culminates in the MAC. The fragments generated along the way mediate lysis, opsonization, and inflammation – all critical processes in immunity and, significantly, in the pathology of hemolytic transfusion reactions

Activating the Cascade: The Pathways

There are two main ways complement gets started that are relevant to us:

Classical Pathway: Antibody-Triggered
- Initiation: Primarily kicked off by antibodies bound to antigens (immune complexes)
  - IgM: Extremely efficient; just one molecule bound to a cell can start it
  - IgG: Less efficient; needs two IgG molecules close together. IgG3 > IgG1 are the best IgG activators; IgG4 doesn’t activate it
- Mechanism: C1 complex (C1q recognizes the antibody Fc region) -> activates C1r -> activates C1s -> C1s cleaves C4 and C2 -> C4b binds to the cell surface -> C2a binds to C4b
- Key Enzyme Formed: C4b2a (Classical Pathway C3 Convertase)
Alternative Pathway: Spontaneous & Surface-Driven
- Initiation: Doesn’t need antibodies. Starts via:
  - Slow, spontaneous “tick-over” of C3 in plasma (C3 -> C3(H2O))
  - Presence of certain activating surfaces (like microbes) that lack protective regulatory proteins found on our own cells
- Mechanism: C3(H2O) or surface-bound C3b binds Factor B -> Factor D cleaves Factor B -> Bb remains bound
- Key Enzyme Formed: C3bBb (Alternative Pathway C3 Convertase). This pathway includes an important amplification loop where the C3bBb complex makes more C3b, which can then form more C3bBb. Stabilized by Properdin

The Central Hub & Terminal Attack

Convergence at C3: Both pathways lead to the formation of a C3 Convertase (C4b2a or C3bBb). This enzyme is crucial because it cleaves large amounts of C3, the most abundant complement protein, into:
- C3a: An anaphylatoxin (inflammation)
- C3b: The major opsonin (tagging for destruction) and key component for the next step
Forming the C5 Convertase: C3b binds to the C3 convertase complex (forming C4b2a3b or C3bBb3b). This new enzyme is the C5 Convertase
The Final Assault (Terminal Pathway)
- C5 Convertase cleaves C5 into:
  - C5a: The most potent anaphylatoxin and chemoattractant
  - C5b: Initiates the assembly sequence
- C5b sequentially recruits C6, C7, C8, and multiple C9 molecules
- This forms the Membrane Attack Complex (MAC, C5b-9), which inserts into the target cell membrane

The Consequences: Biologic Properties

Activation of the complement cascade results in several powerful biological effects:

Cell Lysis (via MAC)
- The MAC (C5b-9) forms pores in cell membranes, disrupting osmotic balance and causing cells to burst
- Result: Intravascular Hemolysis (destruction of RBCs within blood vessels)
- Relevance: Acute HTRs (e.g., ABO mismatch). Visible hemolysis in vitro
Opsonization (via C3b)
- C3b: coats target cells (“tags” them)
- Phagocytes (macrophages in spleen/liver) recognize C3b via complement receptors (CR1) and engulf the cell
- Result: Extravascular Hemolysis (removal of RBCs outside blood vessels)
- Relevance: Delayed HTRs, AIHA. Leads to C3d remaining on cells, detectable by DAT
Inflammation (via C3a, C4a, C5a)
- These anaphylatoxins cause histamine release from mast cells (-> vasodilation, increased permeability) and act as chemoattractants (C5a strongly recruits neutrophils)
- Result: Local and systemic inflammatory symptoms
- Relevance: Fever, chills, hypotension, pain often seen in HTRs
Immune Complex Clearance (via C3b)
- C3b coats circulating immune complexes, allowing them to bind to CR1 on red blood cells for transport to the liver/spleen for disposal by macrophages

Testing

Pathway Mechanisms