How Does Complement System Work?

Complement System Overview

The complement system immunology bridges innate and adaptive immunity. This network of proteins orchestrates critical complement immune responses, ensuring protection against pathogens and maintaining host homeostasis.

What is the Complement System?

The complement network is a complex collection of more than 30 soluble and membrane-bound proteins. They work in concert to seek out, opsonise and destroy pathogens. As an underlying mechanism, immune system complement can be used to support the performance of antibodies and phagocytic cells.

The complement immune system in immunology is a fast-response system that kills pathogens directly by forming a hole in their membranes. Complement proteins are precisely programmed to prevent injury to host tissue, highlighting the precision of this immune protection.

Historical Background of the Complement System

The complement system was identified only in the late 19th century by Jules Bordet, and its function involved antibody-based bacterial lysis. In the subsequent decades, decades of research revealed the importance of complement immunity and revolutionised how we thought about host-pathogen interactions.

• 1890s: Birth of heat-resistant serum factor, aka "complement".
• 1960s: Discussion of the three activation routes (classical, alternative and lectin).
• The Current Era: Advances in complement technology, leading to therapeutic applications targeting complement dysregulation in diseases such as paroxysmal nocturnal hemoglobinuria (PNH) and age-related macular degeneration (AMD).

Biopharmacological Application of the Complement System

The immune complement system is the anti-microbe first line of defence. Profound functions: opsonisation, chemotaxis, direct lysis. The complement system in immunity connects the two arms of the immune response:

• Innate immunity: Antigen recognition and elimination at a speed.
• Adaptive immunity: B cell activation and antibody generation are enhanced.

A new generation of studies has identified the complement system as being responsible for tissue homeostasis, apoptotic cell clearance and inflammation control.

Major Pathways of Complement Activation

Fig. 1 Complement activation pathways and assembly of the terminal pathway.^{1, 2}

There are three primary pathways through which the complement system is activated:

Table. 1 Three primary ways in which the complement system is activated.

Pathway	Trigger	Key Component	Mechanism
Classical Pathway	Activation occurs when antibodies (IgG or IgM) bind to antigens, forming immune complexes.	C1 complex (C1q, C1r, C1s)	C1q binds to the Fc region of the antibody. C1r and C1s are sequentially activated, leading to cleavage of C4 and C2. This generates the C3 convertase, which amplifies the cascade.
Lectin Pathway	Activation is initiated by pattern recognition molecules such as mannose-binding lectin (MBL) or ficolins binding to pathogen-associated molecular patterns (PAMPs).	MBL-associated serine proteases (MASPs)	MASPs cleave C4 and C2, forming the C3 convertase. This pathway is antibody-independent, making it a critical part of innate immunity.
Alternative Pathway	Spontaneous hydrolysis of C3 or direct interaction with pathogen surfaces.	Factor B Factor D Properdin	C3 undergoes spontaneous hydrolysis to form C3(H2O). Factor B binds to hydrolyzed C3, and Factor D cleaves Factor B to generate a fluid-phase C3 convertase. Properdin stabilizes the convertase, amplifying complement activation.

Common Pathway and Terminal Activation

All three pathways converge at the cleavage of C3, leading to:

• Formation of the C5 convertase.
• Activation of the Membrane Attack Complex (MAC), which creates pores in the target cell membrane, resulting in lysis.

Core Functions of the Complement System

The activated complement system does this by means of a series of proteolytic steps that initiate effector molecules. There are three main kinds of functions.

• Pathogen Clearance

  The complement system enhances pathogen clearance through:

  • Opsonization: Proteins of the complement system, specifically C3b, coat pathogens for phagocytosis by macrophages and neutrophils.
  • MAC: A lytic structure composed of C5b-C9 components, which makes holes in pathogen membranes, lysis cell.

• Immune Complex Clearance

The immune complexes are cleared by the complement system. C3b attaches to these complexes, which they then dissolve and clear from the spleen and liver.

Table. 2 Key roles in immune complex handling.

Step	Molecule Involved	Outcome
Immune complex binding	C3b	Solubilization of immune complexes
Transport to phagocytes	CR1	Clearance via liver and spleen

• Regulation of Inflammatory Response

Complement fragments (e.g., C3a, C5a) act as anaphylatoxins, inducing:

• Vasodilation.
• Increased vascular permeability.
• Recruitment of immune cells to the site of infection.

Regulation of Complement System

The complement system's regulation involves several key players and mechanisms, which ensure precise control of activation and termination.

Soluble Regulators

Table. 3 Soluble regulators of complement system.

Regulator	Function	Pathway Targeted
C1 Inhibitor	Inhibits C1r and C1s, preventing activation of the classical pathway	Classical Pathway
Factor H	Promotes C3b inactivation by factor I; prevents alternative pathway amplification	Alternative Pathway
Factor I	Cleaves C3b and C4b to inactive fragments in the presence of cofactors	All Pathways
C4-binding Protein (C4BP)	Accelerates decay of C3 convertase in the classical and lectin pathways	Classical and Lectin Pathways
Vitronectin	Prevents MAC formation by inhibiting C5b-7 complex integration	Terminal Pathway

Membrane-Bound Regulators

Table. 4 Membrane-bound regulators of complement system.

Regulator	Function
CD55 (Decay-Accelerating Factor, DAF)	Disrupts C3/C5 convertase complexes, halting complement system activation
CD46 (Membrane Cofactor Protein, MCP)	Serves as a cofactor for factor I-mediated cleavage of C3b and C4b
CD59 (Protectin)	Inhibits assembly of the MAC

Complement receptors on immune cells also play a regulatory role. For example:

• CR1 (CD35): Seen on erythrocytes, leukocytes and phagocytes; assists with the removal of immune complexes and suppresses overactivation.
• CR3 (CD11b/CD18): Enables phagocytosis and suppresses complement-induced inflammation.

Dysregulation and Associated Disorders

The complement deficiency can lead to pathological conditions.

• PNH - Mutations in PIGA gene; lack of CD55/CD59 expression
• Atypical Hemolytic Uremic Syndrome (aHUS) - Factor H, factor I, or MCP mutations
• AMD - Dysregulated alternative pathway; factor H polymorphisms
• Systemic Lupus Erythematosus (SLE) - Deficiency in early complement components (e.g., C1q)

Effector Functions of the Complement System

Complement activation, regardless of the pathway, converges on the generation of three broad effector pathways that serve to enable the complement to fulfill its physiological imperatives in host defense.

• Opsonization

A primary opsonin called C3b adheres to microbe surfaces and labels organisms for phagocytosis by immune cells, including macrophages and neutrophils. This is an activity that bridges innate and adaptive immunity through improved antigen presentation.

• Chemotaxis and Inflammation

Anaphylatoxins (C3a, C5a) are chemoattractants that attract immune cells to the point of infection. Degranulation of mast cells and basophils by such fragments also encourages inflammation.

• Formation of the MAC

The terminal pathway culminates in the assembly of MAC (C5b-C9), which forms transmembrane pores, leading to osmotic lysis of targeted cells. This is particularly effective against Gram-negative bacteria.

Table. 5 Effector functions of complement fragments.

Fragment	Effector Function
C3b	Opsonization, immune complex clearance
C3a	Anaphylatoxin, induces inflammation
C5a	Strong anaphylatoxin, chemotaxis
MAC (C5b-C9)	Membrane attack and cytolysis

Complement Functions and Diseases

Even though we know that complement protects, the breakdown of the complement system leads to everything from autoimmune disease and infectious disease to cancer.

• Autoimmune disease results from a peculiar immune response to antigens of the self. Complement dysregulation can make these conditions even worse by being activated too strongly or overregulated.
• Complement proteins have dual roles in infections and malignancies, acting as both defenders and facilitators of disease.

Table. 6 Complement roles in disease categories.

Disease Category	Complement Mechanism	Example
Autoimmune Diseases	Aberrant activation and immune complex buildup	SLE, RA
Infectious Diseases	Pathogen evasion of complement attack	Neisseria meningitidis
Cancer	Immunosuppression via complement regulators	Breast, lung cancer

The close relationship between the complement system and disease highlights its dual nature as a guardian and potential adversary of human health. Advances in therapeutic targeting (especially monoclonal antibodies and small molecule inhibitors) have opened up new opportunities for precision medicine. In addition, the development of robust assays for complement activity can help to better study complement-related diseases.

Complement components and split products are invaluable for disease researches. We offer complement testing services, including:

• Complement function test
• Complement autoantibody test
• Complement genetic test
• Complement multiplex assay

If additional help is needed, please directly contact us and consult our technical supports for more detail.

Resources

References

1. Ng, Nicole, and Charles A. Powell. "Targeting the complement cascade in the pathophysiology of COVID-19 disease." Journal of Clinical Medicine 10.10 (2021): 2188.
2. under Open Access license CC BY 4.0, without modification

• What is Complement System?
• Complement Protein Fragment Nomenclature