Complement System and Innate Immunity

1. Initiation of the Complement Cascade

The complement system is triggered through three distinct pathways, each requiring specific molecular initiators:

1. Classical Pathway: Initiated by the binding of $C1$ to antigen-antibody complexes ($IgM$ or $IgG$). This requires a conformational change in the $Fc$ region of the antibody to expose binding sites for $C1$.

2. Alternative Pathway: Initiated by the spontaneous hydrolysis of $C3$ into $C3a$ and $C3b$ in the serum. It proceeds on microbial surfaces that lack inhibitory proteins.

3. MBL (Mannose-Binding Lectin) Pathway: Initiated when MBL recognizes and binds to mannose residues on the surface of pathogens, activating MASP-2 (MBL-associated serine protease), which mimics the function of $C1$.

2. Comparison of the Three Pathways

3. Antibodies and Complement Fixation

Only certain classes of antibodies can initiate the classical pathway:

• Capable Classes: $IgM$ and $IgG$ (specifically $IgG1, IgG2, IgG3$).

• $IgM$ Efficiency: $IgM$ is the most efficient activator because it exists as a pentamer (five units linked together). A single pentameric $IgM$ molecule bound to a pathogen provides enough $Fc$ density for $C1$ to bind. In contrast, $IgG$ is a monomer, requiring at least two $IgG$ molecules to be positioned in close proximity to fix complement.

4. Mechanisms of Microbial Elimination

Complement facilitates the removal of pathogens through three primary mechanisms:

1. Opsonization: Pathogens are coated with $C3b$. Phagocytes (neutrophils and macrophages) have $C3b$ receptors, greatly enhancing their ability to ingest and destroy the microbe.

2. Bacterial Lysis: The assembly of the Membrane Attack Complex (MAC) ($C5b$, $C6$, $C7$, $C8$, and polymerized $C9$) creates transmembrane pores in the bacterial cell wall, leading to osmotic lysis and death.

3. Inflammation: Small fragments ($C3a, C4a, C5a$) act as anaphylatoxins, triggering mast cell degranulation and recruiting immune cells to the site of infection.

5. Classification of Functional Components

Components are categorized by their role in the immune response:

• Opsonization: $C3b$ is the primary opsonin.

• Chemotaxis: $C5a$ is a potent chemoattractant that specifically recruits neutrophils to the site of infection.

• Vascular Changes/Inflammation: $C3a$ and $C5a$ increase vascular permeability by inducing mast cell degranulation and the release of vasoactive amines.

6. Regulation: Mammalian vs. Bacterial Cells

The alternative pathway is self-amplifying but is strictly regulated on host cells to prevent self-damage:

• In Mammalian Cells: Host cells express regulatory proteins like Factors H and I, C4-binding protein, and CD59. Factors H and I degrade $C3b$ on host surfaces, preventing the formation of $C3bBb$ ($C3$ convertase). CD59 specifically prevents the polymerization of $C9$, blocking MAC formation.

• In Bacterial Cells: Bacteria lack these inhibitory molecules. Therefore, when $C3b$ binds to a bacterial surface, it remains stable, binds Factor B, and initiates the cascade leading to lysis.