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Immunology

Pathway Mechanisms

The Complement System isn’t a single cell or molecule, but a complex cascade of over 30 proteins circulating in our blood in an inactive state, just waiting for a trigger

Think of the complement system as a molecular booby trap or a rapid-response demolition team. It’s a critical part of our innate immunity, but it also serves as a powerful bridge to amplify the effects of our adaptive immunity. Its purpose is to rapidly identify and eliminate pathogens and cellular debris. The “demolition” is achieved through a tightly controlled domino effect, or enzymatic cascade, where one activated protein cleaves and activates the next in line

There are three ways to light the fuse on this explosive system—the Classical, Alternative, and Lectin pathways. We’ll focus on the two most clinically significant for the serology lab: the Classical and Alternative pathways. While their triggers are completely different, they both converge to unleash the same powerful effector functions

Classical Pathway: The “Intel-Driven” Targeted Strike

This pathway is a perfect example of how the innate complement system amplifies the specific work of the adaptive immune system. It doesn’t fire randomly; it requires prior “intelligence” in the form of an antibody that has already marked a target

  • The Trigger: The Classical Pathway is activated by the binding of the first complement component, C1, to the Fc (constant) region of an antigen-antibody complex
    • IgM: is the most efficient activator. A single IgM molecule bound to a pathogen is enough to kick off the cascade because its pentameric structure provides multiple Fc binding sites in close proximity
    • IgG: (subclasses 1, 2, and 3) can also activate this pathway, but it requires at least two IgG molecules to be close enough together on the antigen’s surface to provide a stable binding platform for C1
  • The Mechanism (The Initial Dominoes)
    1. The C1 complex (made of C1q, C1r, and C1s) binds to the antibody Fc regions. This binding activates C1s, turning it into an active enzyme
    2. The activated C1s enzyme now has two jobs. First, it cleaves C4 into two pieces: a small inflammatory fragment, C4a, and a larger piece, C4b, which covalently binds to the pathogen’s surface
    3. Next, C1s cleaves C2 into C2a and C2b. The C2a fragment then binds to the surface-bound C4b
    4. This combination, C4b2a, is a new and powerful enzyme called the Classical Pathway C3 Convertase. Its creation is the entire goal of this first stage. Its sole purpose is to find and cleave C3, the most abundant complement protein

Alternative Pathway: The “Proximity Fuse”

This pathway is a more ancient, primitive part of our innate immune system. It doesn’t require any antibodies. Instead, it acts as a constant surveillance system that fires whenever it detects a surface that “looks” foreign and lacks the protective shields that our own cells have

  • The Trigger: This pathway is activated directly by foreign surfaces, such as the lipopolysaccharide (LPS) on the outer membrane of gram-negative bacteria, yeast cell walls, and some viruses. It’s triggered by the absence of “self” markers

  • The Mechanism (The Constant Surveillance)

    1. The central protein, C3, is inherently unstable. In the blood, it is constantly being hydrolyzed at a very low rate in a process called “tick-over,” forming an activated C3b-like molecule
    2. Normally, if this activated C3 lands on one of our own cells, regulatory proteins on our cell surfaces (like DAF) immediately inactivate it, preventing any damage
    3. However, if this activated C3 lands on a pathogen surface, which lacks these protective regulatory proteins, it becomes stabilized
    4. A plasma protein called Factor B then binds to this surface-bound C3b
    5. Another enzyme, Factor D, then cleaves Factor B, forming a complex called C3bBb
    6. This C3bBb complex is the Alternative Pathway C3 Convertase. Just like its classical pathway counterpart, its job is to cleave massive amounts of C3

Convergence and the Common Terminal Pathway: The Grand Finale

Regardless of whether the fuse was lit by an antibody (Classical) or a bacterial surface (Alternative), both pathways result in the creation of a C3 convertase (either C4b2a or C3bBb) on the pathogen’s surface

  • Amplification Loop: The C3 convertase is the centerpiece of the entire system. It cleaves C3 into C3a (a potent inflammatory mediator) and C3b. Each C3b that is created can then bind to the surface and start a new C3bBb complex (via the alternative pathway), creating a massive amplification loop that coats the pathogen in C3b

  • Formation of the C5 Convertase: Some of the newly formed C3b binds directly to the C3 convertase complex itself, creating a C5 convertase (either C4b2a3b or C3bBb3b). This new enzyme’s job is to cleave C5 into C5a and C5b

  • The MAC Attack (The Effector Pathway)

    1. C5b is the initiator. It attaches to the pathogen’s membrane
    2. It then sequentially recruits C6, C7, and C8
    3. This C5b-8 complex inserts into the membrane and triggers the final, dramatic step: the polymerization of up to 18 molecules of C9
    4. These C9 molecules form a hollow tube, a large pore that punches right through the pathogen’s membrane. This structure is the Membrane Attack Complex (MAC)
    5. This pore destroys the pathogen’s osmotic integrity. Water rushes in, the cell swells and bursts. This is called lysis

Three Main Biological Functions (The “Why”)

  1. Opsonization The coating of a pathogen with C3b is the single most important outcome of the complement cascade. Phagocytic cells (like macrophages) have C3b receptors, making C3b-coated pathogens incredibly “tasty” and easy to engulf. C3b is the body’s most potent opsonin
  2. Inflammation The small “a” fragments that are cleaved off—C3a and C5a (and C4a)—are powerful chemical messengers called anaphylatoxins. They act as distress signals, recruiting phagocytes to the area and causing mast cells to release histamine, increasing blood flow and vascular permeability
  3. Lysis The end result of the terminal pathway is the formation of the Membrane Attack Complex (C5b-9), which directly kills pathogens by punching holes in their membranes