The complement system is a network of over 30 proteins throughout the body. These proteins identify and neutralize threats as part of the innate immune system. It acts as an immediate defense, prepared without prior pathogen exposure. This system enhances antibodies and other immune cells to clear microbes and damaged cells. Components, primarily from the liver, circulate as inactive precursors, activated in a cascade upon detecting invaders.
The Three Activation Pathways
The complement system initiates through three distinct pathways, each triggered by different cues, converging on a shared central step. These pathways allow response to various threats. Any pathway’s activation leads to C3 protein cleavage, driving the system’s protective actions.
Classical Pathway
The classical pathway begins when specific antibodies (IgG or IgM) bind to a pathogen, forming an antigen-antibody complex. This allows the C1 complex (C1q, C1r, C1s) to attach. C1r and C1s activate, initiating C4 and C2 cleavages. This forms C4b2a, the C3 convertase, which cleaves C3.
Lectin Pathway
The lectin pathway triggers independently of antibodies when mannose-binding lectin (MBL) or ficolins bind to microbial sugar patterns. These sugars are common on bacteria, fungi, and some viruses, but absent from human cells. Once MBL binds, it associates with activated MBL-associated serine proteases (MASP-1 and MASP-2). MASP-1 and MASP-2 then cleave C4 and C2, forming the C4b2a C3 convertase.
Alternative Pathway
The alternative pathway operates as a continuous surveillance system, constantly active at a low level in the blood. It initiates by spontaneous C3 hydrolysis, generating C3 capable of binding Factor B. Factor D then cleaves Factor B, forming the C3bBb complex, a C3 convertase. This pathway amplifies on foreign cells lacking protective proteins, acting as a robust first line of defense without prior antibody engagement.
Primary Functions of the Complement System
Once activated, the complement system performs several functions to eliminate threats. These actions are distinct from activation triggers and focus on the cascade’s direct consequences. Activated components neutralize pathogens and alert other immune system parts.
Opsonization (Tagging for Disposal)
Opsonization is a primary function, where complement proteins, particularly C3b, coat pathogens. These C3b molecules act as molecular tags. Phagocytic cells (macrophages and neutrophils) recognize C3b via specialized receptors, allowing efficient engulfment and destruction of tagged microbes. This enhances foreign particle clearance by immune cells.
Inflammation (Recruiting Reinforcements)
Small protein fragments, anaphylatoxins (C3a and C5a), are generated during complement activation. These fragments act as chemical alarms, attracting other immune cells, including phagocytes, to the infection site. They also contribute to inflammation by increasing blood vessel permeability, allowing immune cells and fluid to reach affected tissue, aiding threat containment and elimination.
Cell Lysis (Direct Destruction)
The terminal step involves the formation of the Membrane Attack Complex (MAC), a pore-forming structure. This complex assembles from complement proteins (C5b, C6, C7, C8, multiple C9) that insert into the outer membrane of certain pathogens, particularly Gram-negative bacteria. The MAC creates holes in the pathogen’s membrane, disrupting integrity and leading to an uncontrolled influx of water and ions. This osmotic imbalance causes the pathogen to swell and burst, leading to direct destruction.
Regulation of Complement Activity
Given its potent destructive capabilities, the body employs regulatory mechanisms to prevent the complement system from attacking healthy host cells. These controls ensure activation is localized to foreign or damaged cells, protecting self-tissues. This balance is maintained by various soluble and membrane-bound regulatory proteins.
Healthy human cells possess specific regulatory proteins that inactivate inadvertently bound complement proteins. For example, CD59 (protectin) inhibits MAC assembly on host cells, while C1-inhibitor prevents classical pathway activation. Other regulators, like Decay-Accelerating Factor (DAF) and Complement Receptor 1 (CR1), promote C3 convertase dissociation on self-surfaces, preventing cascade amplification.
These regulatory proteins interact with activated complement components, preventing their formation, accelerating their decay, or facilitating their enzymatic degradation by factors like Factor I. Microbes, lacking these mechanisms, remain vulnerable to sustained complement activation. This differential regulation ensures the complement system targets invaders while sparing body tissues.
The Complement System in Health and Disease
While a powerful defender, complement system malfunction can lead to significant health problems. Issues arise from component deficiency or over-activation and dysregulation. Understanding these scenarios helps explain disease presentations and guide therapeutic strategies.
Complement Deficiency
When complement system components are missing or dysfunctional due to genetic mutations, individuals become susceptible to recurrent and severe infections. Deficiencies in early classical pathway components (C1, C2, C4) or C3 often lead to recurrent infections with encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae). Deficiencies in later pathway components (C5-C9) or properdin (alternative pathway) are associated with recurrent Neisseria species infections (Neisseria meningitidis).
Beyond infections, deficiencies in early classical pathway components (C1, C2, C4) are linked to an increased risk of autoimmune conditions, such as systemic lupus erythematosus (SLE). This suggests a role for the complement system in clearing immune complexes and cellular debris, which, if not removed, can contribute to autoimmune responses. Timely diagnosis is important for medical management.
Dysregulation and Over-activation
Conversely, if regulatory “brakes” fail or the system becomes chronically overactive, it can mistakenly attack healthy tissues. This uncontrolled activity contributes to various autoimmune and inflammatory conditions. In these scenarios, the complement system drives tissue damage.
Examples of diseases involving complement dysregulation include atypical hemolytic uremic syndrome (aHUS), a severe kidney disorder where uncontrolled complement activation damages kidney blood vessels. Similarly, glomerulonephritis (kidney inflammation) and age-related macular degeneration (AMD), a leading cause of vision loss, also involve inappropriate complement activity. In conditions like lupus, complement activation can contribute to tissue injury by forming harmful immune complexes that deposit in organs.