IaD [009] complement and phagocytosis

Complement Factors

  • The complement system comprises a complex array of heat-labile proteins found in blood and tissue fluids, crucial for the immune response. Most of these components are synthesized in the liver, resulting in a total of over 30 proteins specific to this system.

  • Basic complement proteins consist of C1 through C9, along with factors B, D, and properdin (P). Furthermore, regulatory proteins play an essential role in preventing unregulated complement activation, which could damage host tissues.

Complement System Functionality

  • The complement system significantly enhances the capability of antibodies and phagocytic cells in the clearance of microbes, promoting inflammation, and facilitating the attack on pathogens' cell membranes. It serves as a critical intersection between the innate and adaptive immune systems, as it can be activated by antibodies produced during adaptive immunity.

Activation of Complement

  • Complement components circulate in an inactive form designated as C1, C2, ... C9, awaiting activation. The activation occurs sequentially through interaction between complement factors, which initiate a cascade known as the complement activation cascade.

  • Upon activation, specific factors cleave into two fragments: the small fragment (e.g., C2a) functions as a by-product, while the large fragment (e.g., C2b) continues the activation process and plays an active role in the immune response.

Pathways of Complement Activation

Classical Pathway

  • Initiated by the formation of immune complexes (antigen-antibody complexes) that activate the complement component C1, comprising sub-components C1q, C1r, and C1s. Upon binding to an antibody on its antigen, this triggers the enzymatic cleavage of C4 and C2, leading to the formation of a C3 convertase (C4b2a).

  • The C3 convertase then cleaves C3 into C3a and C3b, propagating further activation events and enabling the formation of the membrane attack complex (MAC), which is crucial for cell lysis.

Late Lytic Phase of Complement Activation

  • This phase commences with the cleavage of C5 into C5a and C5b. The C5b fragment subsequently binds to complement components C6, C7, C8, and C9, culminating in the formation of the MAC. This complex penetrates the target cell membrane, resulting in an uncontrolled influx of water and solutes, leading to osmotic lysis and the destruction of microbial cells.

Lectin Pathway

  • Activated when mannose-binding lectin (MBL) binds to specific mannose residues on microbial surfaces. This interaction activates serine proteases MASP-1 and MASP-2, paralleling the mechanisms seen in the classical pathway. Like this pathway, it generates C3 convertase, facilitating the complement cascade.

Alternative Pathway

  • This pathway remains continuously activated at low levels due to spontaneous hydrolysis of C3, setting it apart from the classical and lectin pathways as it does not require antibodies for its initiation. The binding of C3b to microbial surfaces amplifies the complement response by forming a unique C3 convertase (C3bBb) that utilizes complement components C3b, factor B, factor D, and properdin for enhanced activation and subsequent MAC formation.

Functions of Complement

  • Direct Microbial Cytolysis: The MAC effectively kills bacteria and tumor cells by disrupting their cell membranes.

  • Opsonization: The deposition of C3b on pathogens enhances phagocyte recognition and attachment, facilitating more efficient ingestion by immune cells.

  • Immune Complex Clearance: C3b marking immune complexes allows red blood cells (RBCs) to transport these complexes to the spleen and liver for phagocytic clearance.

  • Inflammatory Response: By-products from the complement activation, like C3a, C4a, and C5a, contribute to the degranulation of mast cells, recruitment of additional phagocytes, and increase in local blood vessel permeability, all of which are vital for inflammation.

Regulation of Complement Pathway

  • It is critical to regulate complement activity to prevent damage to host tissues. Regulation occurs through:

    • Passive mechanisms: Inactivation of components without external stabilization.

    • Active mechanisms: Involvement of specific regulatory proteins that inactivate complement components, such as CD59, which protects host cells from MAC formation.

Diseases Associated with Complement System

  • Deficiencies in various complement components can result in heightened vulnerability to infections. Conversely, abnormal regulatory mechanisms may lead to tissue damage, contributing to autoimmune diseases and inflammatory conditions.

Phagocytosis Mechanisms

  • Key phagocytes include neutrophils, monocytes/macrophages, and dendritic cells.

  • Killing mechanisms among phagocytes can be classified into:

    • Oxidative Killing: Involves reactive oxygen species (ROS) generated to indiscriminately kill microbes.

    • Non-oxidative Killing: Utilizes substances like lysozyme and defensins to neutralize pathogens.



Case-Based Questions on the Complement System

  1. A 45-year-old woman presents with recurrent infections, including meningitis. Laboratory tests reveal low levels of complement component C3. What is the most likely underlying issue?

    • A) Genetic deficiency in C3

    • B) Overactivation of the classical pathway

    • C) Autoimmune destruction of complement components

    • D) Excessive production of C3 regulatory proteins

    • E) High levels of complement inhibitors

  2. A patient with a history of systemic lupus erythematosus (SLE) has a sudden worsening of symptoms. Laboratory tests show elevated levels of C3a and C5a. What is the most likely cause of his condition?

    • A) Decreased complement activation

    • B) Overactivity of the complement system

    • C) Lack of antibodies

    • D) Deficiency of the alternative pathway

    • E) Increased levels of complement regulatory proteins

  3. A 60-year-old male suffers from a chronic inflammatory condition characterized by joint pain and swelling. Tests show a high concentration of anaphylatoxins. Which pathway of the complement system is most likely being activated?

    • A) Classical pathway

    • B) Lectin pathway

    • C) Alternative pathway

    • D) All pathways equally

    • E) None of the pathways

  4. A child presents with infections by encapsulated bacteria. Genetic tests reveal a deficiency in complement component C4. Which pathway is primarily affected?

    • A) Alternative pathway

    • B) Classical pathway

    • C) Lectin pathway

    • D) Both classical and lectin pathways

    • E) All pathways

  5. During an examination, a sample from a patient shows the presence of the membrane attack complex (MAC). Which complement components are directly associated with forming this complex?

    • A) C1, C2, C3

    • B) C4, C5, C6

    • C) C5b, C6, C7, C8, C9

    • D) C3a, C3b

    • E) C1q, C1r, C1s

  6. A lab technician observes that serum from a healthy individual has no C3 convertase activity. What is the most relevant conclusion?

    • A) The lectin pathway is inactive

    • B) The alternative pathway is functioning correctly

    • C) The classical pathway is impaired

    • D) There is no need for complement activity

    • E) All complement pathways are activated

  7. A patient develops an autoimmune disease with excessive tissue damage. Further examination reveals overexpression of CD59. Which of the following situations is most likely occurring in this patient?

    • A) Reduced complement activation

    • B) Excessive regulation of complement activity

    • C) Increased formation of MAC

    • D) Impaired phagocytosis

    • E) Deficiency of opsonization

  8. A young adult with a history of recurrent respiratory infections is diagnosed with a deficiency in factor D. What system effect does this have?

    • A) Impaired classical pathway

    • B) Impaired alternative pathway

    • C) Impaired lectin pathway

    • D) Deficiency in immunoglobulins

    • E) Decreased opsonization

  9. An elderly patient presents with systemic inflammation, and serum tests reveal significant amounts of C3a. What type of immune response is most likely occurring?

    • A) Decreased phagocytosis

    • B) Inhibition of the complement system

    • C) Enhanced inflammatory response

    • D) Inhibition of antibody production

    • E) Lack of immune complexes

  10. A researcher isolates a compound that inhibits MASP-1 and MASP-2. Which complement pathway would be directly affected?

  • A) Classical pathway

  • B) Alternative pathway

  • C) Lectin pathway

  • D) All pathways

  • E) None of the pathways

  1. A newborn exhibits signs of immune deficiency. Testing shows low levels of complement proteins and increased susceptibility to infections. Which supplement may be beneficial?

  • A) Antibodies

  • B) Complement proteins

  • C) Vitamins

  • D) Non-specific antibiotics

  • E) Interferons

  1. An athlete experiences delayed onset muscle soreness after exercise. High levels of C5a are observed in his serum. What role does C5a play in this physiological response?

  • A) Causes muscle damage

  • B) Initiates vasodilation

  • C) Enhances phagocyte recruitment

  • D) Inhibits inflammation

  • E) Increases energy production

  1. A patient presenting for routine surgery has been previously diagnosed with a complement component deficiency. The surgeon is concerned about infection. Which component should be monitored closely during the procedure?

  • A) C1

  • B) C3

  • C) C4

  • D) C5

  • E) C9

  1. A study reveals that high temperatures decrease the activity of complement proteins in vitro. What condition would you expect to occur in patients during fever?

  • A) Increased infection risk

  • B) Autoimmune disease

  • C) Enhanced immune response

  • D) Reduced vaccine effectiveness

  • E) Increased tissue damage

  1. A clinical trial investigates a new drug that enhances complement activity. Which of the following conditions could this drug potentially exacerbate?

  • A) Hypocomplementemia

  • B) Autoimmune diseases

  • C) Complement deficiencies

  • D) Infections

  • E) Allergic reactions


  1. A) Genetic deficiency in C3

  2. B) Overactivity of the complement system

  3. A) Classical pathway

  4. D) Both classical and lectin pathways

  5. C) C5b, C6, C7, C8, C9

  6. C) The classical pathway is impaired

  7. B) Excessive regulation of complement activity

  8. B) Impaired alternative pathway

  9. C) Enhanced inflammatory response

  10. C) Lectin pathway

  11. B) Complement proteins

  12. C) Enhances phagocyte recruitment

  13. B) C3

  14. A) Increased infection risk

  15. B) Autoimmune diseases