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The Complement System: Activation Pathways and Biological Functions

February 24, 2025

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The Complement System: Mechanisms of Activation and Its Crucial Role in Immunity

Introduction

The complement system is an essential component of the innate immune system that enhances the ability of antibodies and phagocytic cells to clear pathogens. It consists of over 30 proteins that work in a cascade mechanism to mediate various immune responses, including inflammation, opsonization, and cell lysis. The system operates through three primary activation pathways—classical, alternative, and lectin—each triggered by different stimuli but converging to produce a common immune response.

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Activation Pathways of the Complement System

1. Classical Pathway

Triggered by antigen-antibody complexes (mainly IgG and IgM)
C1 complex (C1q, C1r, C1s) binds to the Fc region of antibodies
C1s cleaves C4 and C2 to generate C4b2a (C3 convertase)
C3 convertase cleaves C3 into C3a (inflammatory mediator) and C3b (opsonin)
C3b binds to C4b2a, forming C5 convertase (C4b2a3b)
C5 convertase cleaves C5 into C5a (pro-inflammatory) and C5b (initiates the Membrane Attack Complex, MAC)

2. Alternative Pathway

Activated by microbial surfaces (lipopolysaccharides, endotoxins, and fungi)
Spontaneous hydrolysis of C3 into C3(H2O) allows Factor B binding
Factor D cleaves Factor B into Bb, forming C3 convertase (C3bBb)
C3bBb is stabilized by Properdin, amplifying the response
C3 convertase cleaves more C3, leading to formation of C5 convertase (C3bBbC3b)
Initiates the MAC (C5b-C9), which creates pores in pathogen membranes

3. Lectin Pathway

Activated by pathogen-associated carbohydrate patterns (mannose and N-acetylglucosamine)
Mannose-binding lectin (MBL) or ficolins bind to microbial surfaces
MBL-associated serine proteases (MASP-1 and MASP-2) activate and cleave C4 and C2
Forms C4b2a, the same C3 convertase as in the classical pathway
Proceeds similarly, leading to MAC formation

Biological Functions of the Complement System

1. Opsonization

C3b and C4b coat pathogens, marking them for phagocytosis
Facilitates recognition and engulfment by macrophages and neutrophils

2. Cell Lysis via Membrane Attack Complex (MAC)

Terminal complement proteins (C5b, C6, C7, C8, C9) form a pore in the pathogen membrane
Leads to osmotic imbalance and lysis of the target cell

3. Inflammatory Response

C3a, C4a, and C5a act as anaphylatoxins
Induce vasodilation, increase vascular permeability, and recruit immune cells
C5a is a potent chemoattractant for neutrophils and monocytes

4. Immune Complex Clearance

Complement components aid in the removal of immune complexes
Prevents deposition in tissues, reducing inflammation-related damage

5. Bridging Innate and Adaptive Immunity

Enhances B-cell activation through complement receptors (CR2/CD21)
Supports antigen presentation to T cells by dendritic cells

Complement System Regulation and Inhibition

To prevent excessive or self-targeted activation, the complement system is tightly regulated by inhibitory proteins:

Factor H and Factor I: Inhibit the alternative pathway by degrading C3b
CD55 (Decay-Accelerating Factor, DAF): Prevents formation of C3 convertase
CD59 (Protectin): Blocks MAC assembly on host cells

Clinical Significance of the Complement System

1. Complement Deficiencies

C3 deficiency: Increased susceptibility to bacterial infections
C5-C9 deficiencies: Increased risk of Neisseria infections
Factor H deficiency: Associated with atypical hemolytic uremic syndrome (aHUS)

2. Autoimmune Diseases

Systemic lupus erythematosus (SLE): Immune complex deposition due to complement deficiency
Rheumatoid arthritis (RA): Complement-mediated joint inflammation

3. Therapeutic Targeting of the Complement System

Eculizumab (Soliris): C5 inhibitor used in paroxysmal nocturnal hemoglobinuria (PNH)
C1 inhibitors: Used in hereditary angioedema

Conclusion

The complement system is a vital component of immunity, providing defense against pathogens, mediating inflammation, and bridging innate and adaptive immunity. However, dysregulation can contribute to autoimmune diseases and inflammatory disorders, making complement-targeted therapies an important area of biomedical research.

Relevant Website Links

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MCQs on The Complement System: Activation Pathways and Biological Functions

1. What is the primary function of the complement system?

A) Hormonal regulation
B) Blood clotting
C) Immune defense against pathogens
D) Oxygen transport

✅ Answer: C) Immune defense against pathogens
Explanation: The complement system is a part of the innate immune system that enhances the ability of antibodies and phagocytic cells to clear pathogens.

2. The complement system consists mainly of:

A) Carbohydrates
B) Proteins
C) Lipids
D) Nucleic acids

✅ Answer: B) Proteins
Explanation: The complement system comprises a group of serum proteins that function in a cascade to help the immune response.

3. How many pathways activate the complement system?

A) One
B) Two
C) Three
D) Four

✅ Answer: C) Three
Explanation: The three activation pathways are the classical pathway, alternative pathway, and lectin pathway.

4. The classical pathway of complement activation is initiated by:

A) Antibody-antigen complexes
B) Mannose-binding lectin
C) Spontaneous hydrolysis of C3
D) Macrophages

✅ Answer: A) Antibody-antigen complexes
Explanation: The classical pathway is triggered when antibodies (IgG or IgM) bind to antigens, activating C1.

5. The alternative pathway is mainly activated by:

A) IgG
B) Microbial surfaces
C) T-cell receptors
D) Histamines

✅ Answer: B) Microbial surfaces
Explanation: The alternative pathway is activated by spontaneous hydrolysis of C3, which binds to pathogen surfaces.

6. The lectin pathway is activated by:

A) IgM
B) C-reactive protein
C) Mannose-binding lectin (MBL)
D) Phagocytosis

✅ Answer: C) Mannose-binding lectin (MBL)
Explanation: MBL recognizes specific carbohydrate patterns on pathogens, activating the lectin pathway.

7. The complement component that is central to all three activation pathways is:

A) C1
B) C3
C) C5
D) C9

✅ Answer: B) C3
Explanation: C3 is the key component that gets cleaved into C3a and C3b, leading to opsonization, inflammation, and membrane attack.

8. What is the function of C3b in the complement system?

A) Acts as an opsonin
B) Induces fever
C) Forms membrane attack complex
D) Inhibits phagocytosis

✅ Answer: A) Acts as an opsonin
Explanation: C3b binds to microbial surfaces, tagging them for phagocytosis by immune cells.

9. Which of the following is responsible for forming the Membrane Attack Complex (MAC)?

A) C1, C2, C3
B) C5, C6, C7, C8, C9
C) C3, C4, C5
D) Properdin

✅ Answer: B) C5, C6, C7, C8, C9
Explanation: These components form a pore-like structure in pathogen membranes, leading to cell lysis.

10. Which complement component acts as a chemotactic factor for neutrophils?

A) C1q
B) C3b
C) C5a
D) C9

✅ Answer: C) C5a
Explanation: C5a is a potent anaphylatoxin and chemotactic factor that attracts neutrophils to the infection site.

11. Which complement protein regulates the alternative pathway?

A) Properdin
B) C1q
C) IgG
D) C9

✅ Answer: A) Properdin
Explanation: Properdin stabilizes the C3 convertase in the alternative pathway, prolonging its activity.

12. What is the role of C1 inhibitor (C1-INH)?

A) Enhances complement activation
B) Prevents spontaneous activation of complement
C) Forms MAC complex
D) Deactivates IgG

✅ Answer: B) Prevents spontaneous activation of complement
Explanation: C1-INH regulates the classical pathway by inhibiting C1 protease activity.

13. A deficiency in C3 leads to:

A) Increased susceptibility to bacterial infections
B) Autoimmune diseases
C) Increased antibody production
D) Delayed wound healing

✅ Answer: A) Increased susceptibility to bacterial infections
Explanation: C3 deficiency impairs opsonization and MAC formation, making individuals prone to infections.

14. The complement system is part of which type of immunity?

A) Adaptive immunity
B) Innate immunity
C) Passive immunity
D) Cell-mediated immunity

✅ Answer: B) Innate immunity
Explanation: The complement system provides a non-specific defense mechanism against pathogens.

15. Which of the following complement components promotes inflammation?

A) C3a and C5a
B) C1q and C4b
C) C6 and C7
D) C9 and C1q

✅ Answer: A) C3a and C5a
Explanation: These act as anaphylatoxins, triggering inflammation and recruiting immune cells.

16. The role of decay-accelerating factor (DAF) is to:

A) Enhance complement activity
B) Inhibit formation of C3 convertase
C) Activate the lectin pathway
D) Promote phagocytosis

✅ Answer: B) Inhibit formation of C3 convertase
Explanation: DAF prevents excessive complement activation, protecting host cells.

17. The terminal complement pathway is associated with:

A) Antibody production
B) Formation of the MAC complex
C) T-cell activation
D) Histamine release

✅ Answer: B) Formation of the MAC complex
Explanation: The terminal pathway forms the MAC, which lyses pathogen membranes.

18. Hereditary angioedema is caused by a deficiency of:

A) C1-INH
B) C5b
C) Properdin
D) C9

✅ Answer: A) C1-INH
Explanation: C1-INH deficiency leads to uncontrolled complement activation, causing severe swelling.

19. Complement activation can result in:

A) Cell lysis
B) Phagocytosis
C) Inflammation
D) All of the above

✅ Answer: D) All of the above
Explanation: Complement plays multiple roles, including lysing pathogens, opsonization, and inflammation.

20. Which complement pathway is antibody-independent?

A) Classical
B) Alternative
C) Both classical and lectin
D) None

✅ Answer: B) Alternative
Explanation: The alternative pathway does not require antibodies for activation.