How is Complement System Activated

Overview of the Complement System

The complement system is made up of more than 30 proteins which lie in an inactive proenzyme state in the blood. These elements can be broken down into the following groups.

Table. 1 Proteins and their functions of different pathways in the complement system.

The complement system has diverse and vital roles in immunity, ranging from direct pathogen elimination to immune system regulation. These functions can be broadly categorized as follows:

• Opsonization
• Inflammation
• Pathogen lysis
• Immune complex clearance
• Bridging innate and adaptive immunity

Pathways of Complement Activation

What is Complement Activation?

Inherent and acquired immunity involve both complement system activation. After activation of complement, complement can help antibodies and phagocytes rid the body of microbes and infected cells and inflame the body.

Central to complement system are the three primary complement pathways of complement activation: classical pathway, lectin pathway, and alternative pathway. Each pathway is distinct in its initiation mechanisms but converges in a common terminal pathway that results in MAC formation.

Fig. 1 Complement pathway diagram.^{1, 2}

Complement Activated in Classical Pathway

The classical pathway for complement activation is initiated by:

• Initiation
  • C1 complex (C1q, C1r, C1s) binds to the Fc region of IgG or IgM in immune complexes.
  • C1q recognizes and binds to antibodies, triggering a conformational change.
• Enzymatic activation
  • Activated C1r cleaves and activates C1s, which in turn cleaves C4 and C2.
• C3 convertase formation
  • C4b binds C2a, forming the classical C3 convertase (C4b2a).
• Amplification
  • The C3 convertase cleaves C3 into C3a (anaphylatoxin) and C3b, which opsonizes pathogens and facilitates phagocytosis.

Complement Activated in Alternative Pathway

The MBL lectin pathway of complement system is initiated independently of antibodies, relying on pattern recognition molecules to identify carbohydrate structures on microbial surfaces.

• Recognition
  • MBL or ficolins bind specific carbohydrate patterns on pathogens.
• Enzymatic activation
  • MBL-associated serine proteases (MASPs) are activated upon binding, cleaving C4 and C2.
• C3 convertase formation
  • Similar to the classical pathway, C4b2a is formed and acts as the C3 convertase.

Complement Activated in Lectin Pathway

The alternative pathway of complement system is unique in its ability to spontaneously activate without specific triggers, relying instead on constant low-level hydrolysis of C3 in the plasma.

• Spontaneous hydrolysis
  • C3 undergoes hydrolysis to form C3(H₂O), which binds Factor B.
• Amplification loop
  • Factor D cleaves Factor B into Bb, forming the C3 convertase (C3bBb) stabilized by Properdin.
• C3 convertase action
  • Cleavage of additional C3 molecules amplifies the response.
• C5 convertase formation
  • Addition of another C3b to C3bBb forms the C5 convertase (C3bBbC3b).

Serine Proteases in Activation Pathways of Complement System

Activated complement involves a very strong degree of amplification. Serine proteases play an important role in human physiology and pathology, activating each other to promote initiation and amplification of the complement cascade. They have a common domain that contains the catalytic triad of histidine, aspartic acid and serine residues. The serine proteases of the complement system include C1r, C1s, MASPs, C2 of the classical/lectin complement pathway, and Factor B, Factor D, and Factor I.

Key Molecular Events in Complement Activation Pathways

The complement pathway activation involves precisely coordinated molecular events that culminate in pathogen elimination, inflammation modulation, and immune complex clearance.

Table. 2 Key molecular components and their functions.

Regulation of Complement Activation

Precise regulation of complement activation is essential, as inappropriate activation can lead to host tissue damage and various pathological conditions.

Table. 3 Complement regulation pathways.

Fluid-Phase Regulators

The regulation of complement activation in plasma involves several key proteins.

• Factor H - Target alternative pathway
• C4b-binding protein - Target classical pathway complement system
• Carboxypeptidase N - Target anaphylatoxin regulation
• C1 inhibitor - Target classical pathway
• Properdin - Target alternative pathway

Membrane-Bound Regulators

Cell surfaces are protected by membrane-bound complement regulatory proteins.

Table. 4 Membrane-bound complement regulatory proteins.

Molecular Mechanisms of Regulation

• Decay acceleration

Decay-accelerating factors promote the dissociation of C3/C5 convertases, preventing amplification of the complement cascade. This mechanism is particularly important in protecting host cells from complement-mediated damage.

• Enzymatic degradation

The regulation of complement activation heavily relies on specific enzymatic processes. The regulation of C3 and C5 convertases represents a critical control point in the complement cascade pathways.

• Cofactor activity

Several regulatory proteins serve as cofactors for Factor I-mediated cleavage of C3b and C4b, including Factor H, MCP (CD46), CR1 (CD35), C4BP.

Complement Activation in Diseases

The complement system is the centre of the immune system. When this system is engaged, its effects are profound for health and illness.

• Complement activation in autoimmune diseases
  In autoimmune diseases, abnormal complement activity drives tissue damage and disease. Complement activation causes immune complexes to cling to tissues and induce chronic inflammation and cell death.
• Complement activation in infectious diseases
  Over-activation or unsupervised stimulation can cause complement-induced tissue destruction. That's especially true in sepsis, where high complement levels cause endothelial cell destruction, vascular collapse and organ failure.
• Complement Activation in Cancer Immunotherapy
  Both hyperacute rejection and acute rejection are complement-mediated damage. The transplantation application of complement inhibitors - C1 esterase inhibitors for example - is designed to prevent rejection and prolong the life of grafts.
• Complement Activation in in Transplantation Medicine
  Hyperacute rejection and acute rejection are both associated with complement-mediated damage. The use of complement inhibitors in transplantation, such as C1 esterase inhibitors, aims to reduce the risk of rejection and improve graft survival.
• Complement Activation and Therapeutic Approaches
  It is one of the new potential therapeutic targets for the complement system pathways. Drugs inhibit complement activation at various points, particularly C5, preventing the formation of the MAC and reducing downstream tissue damage.

Table. 5 Current complement-targeted therapies.

Creative Biolabs provides comprehensive complement-related products and complement testing services, including but not limited to:

• Total Complement Activity Test
• Individual Components Activity Test
• Complement Activation Products Test
• Antibodies Products
• Sera Products
• Aptamer Products
• Protein Products

Resources

Complement Testing Services

Complement Therapeutics Services Brochure

Podcast

References

1. Detsika, M. G., et al. "The complement cascade in lung injury and disease." Respiratory Research 25.1 (2024): 20.
2. under Open Access license CC BY 4.0, without modification

• Complement System Overview
• Complement System Composition
• Complement System Structure
• Complement System Effector Functions
• Complement System Antibody Introduction
• Complement-Dependent Cytotoxicity
• Complement Activation Definition
• How is Complement Activated in Classical Pathway
• How is Complement Activated in Alternative Pathway
• How is Complement Activated in Lectin Pathway
• Serine Proteases of Complement System