The human immune system is the body’s intricate defense mechanism, safeguarding against threats. Within this network, the complement system is a crucial component of innate immunity, acting as a first line of defense. This system comprises proteins circulating in the blood, identifying and neutralizing invading microorganisms and removing damaged cells. It initiates protective actions without requiring prior exposure to a specific pathogen.
The Complement System: An Immune Overview
The complement system orchestrates immune responses, eliminating harmful substances. One primary function is opsonization, where complement proteins coat pathogens. This labeling makes invaders more recognizable to phagocytic cells like macrophages and neutrophils, which then engulf and destroy them.
Beyond marking targets, the complement system can directly kill pathogens through lysis. This occurs when complement proteins form a membrane attack complex (MAC) on target cells, creating pores that disrupt cell integrity and lead to destruction. Complement activation also generates fragments that recruit other immune cells to infection or injury sites, amplifying the inflammatory response.
Understanding the Alternative Pathway
The alternative complement pathway has a capacity for continuous, low-level activation, often called “tick-over.” This spontaneous activation occurs when the central complement protein, C3, undergoes hydrolysis in the bloodstream, forming C3(H2O). This modified C3 then binds to Factor B, a circulating protein.
Once Factor B binds to C3(H2O), Factor D cleaves it, releasing fragment Ba and leaving Bb associated with C3(H2O). The resulting C3(H2O)Bb complex serves as a C3 convertase, an enzyme capable of cleaving more C3 into C3a and C3b. The C3b fragment is highly reactive and can covalently attach to nearby surfaces, including pathogens or host cells.
C3b attachment to a surface initiates an amplification loop. Surface-bound C3b binds another Factor B molecule, which Factor D cleaves to form C3bBb. This C3bBb complex is a potent and stable alternative pathway C3 convertase. Properdin, a positive regulatory protein, further enhances its stability by binding to and stabilizing the C3bBb complex, allowing it to cleave more C3 and propagate the cascade.
Key Triggers of the Alternative Pathway
The alternative pathway recognizes and responds to foreign surfaces, making it a crucial component of immediate innate immunity. A primary trigger is microbial surfaces, which often lack regulatory proteins found on healthy host cells. For instance, lipopolysaccharide (LPS) in Gram-negative bacteria’s outer membrane is a potent activator. Its unique structure allows C3b to deposit and form stable C3 convertases without rapid inactivation.
Fungal cell wall components, like zymosan, also initiate alternative pathway activation. These carbohydrates provide a suitable surface for stable C3b deposition, leading to active C3 convertase formation. Viral envelopes and parasite surfaces also activate the pathway by promoting C3b binding and preventing its rapid breakdown. The absence of host regulatory proteins on these foreign surfaces allows C3b to accumulate and amplify the complement cascade.
Damaged or altered host cells can also trigger the alternative pathway. When cells undergo necrosis or apoptosis, they may expose molecules not typically accessible. These exposed molecules, such as altered phospholipids or cellular debris, act as platforms for C3b deposition and pathway activation. This helps the immune system clear unhealthy host cells, preventing further tissue damage. The pathway’s ability to discriminate between healthy and altered self-surfaces is fundamental to its protective role.
Regulation of the Alternative Pathway
Given its spontaneous activation, the alternative pathway requires stringent regulation to prevent damage to healthy host tissues. The body employs soluble and membrane-bound regulatory proteins to control complement activation on self-surfaces. Soluble regulators like Factor H circulate in the blood, binding to C3b on host cells and promoting its inactivation by Factor I. Factor I cleaves C3b into inactive fragments, preventing convertase formation.
Membrane-bound regulatory proteins are expressed on host cell surfaces, providing localized protection. Examples include Decay-accelerating factor (DAF, CD55) and Membrane Cofactor Protein (MCP, CD46). DAF accelerates the dissociation of the alternative pathway C3 convertase (C3bBb), dismantling the complex. MCP acts as a cofactor for Factor I, facilitating C3b cleavage and inactivation on host cell surfaces.
CD59 (Protectin) is another membrane-bound regulator that prevents the final assembly of the membrane attack complex (MAC). CD59 inserts into the cell membrane, inhibiting C9 polymerization and blocking pore formation that would lyse the host cell. These mechanisms ensure the alternative pathway primarily targets pathogens and damaged cells, leaving healthy host cells unharmed.