Immunology Chapter 5 Flashcards

The Complement System Overview

• Complement consists of serum and membrane proteins that play crucial roles in immune response, pathogen recognition, and elimination.
• It functions through three main pathways: classical, lectin, and alternative.

Key Terms and Definitions

• Complement: A protein group essential in innate and adaptive immunity, facilitating pathogen elimination.
• Zymogen: Inactive precursor proteins activated by proteolytic cleavage.
• Opsonin: Substances that increase phagocytosis by marking pathogens for destruction.
• Anaphylatoxins (C3a and C5a): Fragment products that cause mast cell degranulation, smooth muscle contraction, and increased vascular permeability.
• Degranulation: Release of contents from mast cells, contributing to inflammation.
• Mast Cells: Cells that release histamines, promoting inflammatory responses.
• Basophils: Leukocytes that produce histamine during immune responses.

Complement Pathways and Their Initiation

• Classical Pathway: Activated by antibody-antigen complexes and involves complement components C1, C4, and C2.
• Lectin Pathway: Initiated by mannose-binding lectin binding to microbial surfaces, activating C2 and C4.
• Alternative Pathway: Starts by the spontaneous hydrolysis of C3, independent of antibodies, leading to C3 convertase formation.

Enzyme Complexes and Their Functions

• C3 Convertase: Enzyme that cleaves C3 into C3a (inflammatory mediator) and C3b (opsonin).
• C5 Convertase: Enzyme complex formed from C3 convertase, cleaving C5 into C5a and C5b, leading to the formation of the membrane attack complex (MAC).

Complement Components and Their Synthesis

• Most complement proteins are synthesized in the liver by hepatocytes.
• Key Components: Include initiators (C1q, MBL), convertase activators, opsonins, anaphylatoxins, MAC, complement receptors, and regulatory proteins.

Differential Pathway Details

• Classical Pathway:
  • Activated by IgM/IgG binding to multivalent antigens.
  • Results in the formation of active serine proteases that cleave C3.
• Lectin Pathway:
  • Initiated by lectins binding to carbohydrates on pathogens.
  • Uses MASP-2 for the cleavage of C2 and C4 to form C3 convertase.
• Alternative Pathway:
  • Activates C3bBb complex providing C3 convertase activity.
  • Amplified through continuous C3 hydrolysis.

Opsonization and Phagocytosis

• Complement proteins (C3b and C4b) bind to microbial cells, enhancing phagocytosis through opsonization.
• C3b facilitates the clearance of immune complexes by either phagocytosis or hepatic clearance.

Regulatory Proteins

• Protect host cells from complement-mediated damage.
• Examples include Factor I, which degrades C3b, and CD59, which inhibits MAC formation on host cells.

Significance of C3

• Central component across all complement pathways.
• Deficiencies in C3 can lead to increased susceptibility to both gram-positive and gram-negative bacteria due to impaired opsonization.

Pathway Comparisons

• Similarities: All pathways converge to generate C3 convertases.
• Differences: Initial activation differs; classical and lectin pathways depend on antibodies or lectins, while alternative pathway activation is spontaneous.

Overall Functions of the Complement System

• Promotes inflammation and enhances immune efficiency via opsonization, chemotaxis, and direct lysis of pathogens through MAC formation.
• Essential for clearing immune complexes and defective cells, contributing to overall homeostasis and immune surveillance.### Activation of Complement Pathways
• Alternative pathway activated in the presence of bacteria through binding of properdin to bacterial surfaces.
• All three complement pathways converge at the formation of C5 convertase, crucial for cleaving C5 into C5a and C5b.
• Classical and lectin pathways’ C5 convertase composition: C4b2a3b; alternative pathway composition: C3bBbC3b.

C5 Fragment and Membrane Attack Complex (MAC)

• C5b is the larger fragment, generated on target cell surfaces, providing binding sites for MAC components.
• C5b rapidly becomes inactive unless stabilized by C6 binding.
• Membrane attack complex formation occurs when C5b binds to C6 and C7, triggering C7 to insert into microbial membranes, leading to cell death.

Consequences of MAC Release

• Released MACs can cause lysis of nearby innocent bystander cells.
• MAC formation prevents osmotic integrity in target cells, resulting in cellular death.

Functions of Complement Components

• The MAC (C5b-C9) is responsible for lysing bacterial cells and disrupting cell membranes.
• C3b and C4b facilitate opsonization, marking pathogens for destruction by immune cells.
• Anaphylatoxins C3a and C5a induce inflammation and chemotaxis through their receptors on leukocytes.

Interface Between Innate and Adaptive Immunity

• C3b and C4b, along with their fragments, augment antibody responses and enhance immunologic memory by interacting with immune complexes.
• MBL, C1q, and complement components C3, C4, and C5a boost antigen presentation, influencing T cell potential.

Immune Response Phases

• Complement components play roles in the clearance of immune complexes and apoptotic cells, especially during the contraction phase of immune responses.
• CD46 promotes the induction of regulatory T cells, essential for maintaining immune homeostasis.

Complement Receptors and Immune Complex Handling

• CR1 (CD35) binds to C3b, C4b, C1q, and MBL, facilitating the clearance of immune complexes via erythrocyte transport to the liver for phagocytosis.
• Phagocyte CR1 receptors mediate binding to complement-opsonized microbes, leading to receptor-mediated phagocytosis and pro-inflammatory molecule secretion.

C3b Breakdown and B Cell Activation

• C3b is broken down by endogenous proteases into iC3b, C3d, and C3dg, each recognized by CD21 (CR2).
• CD21 functions as part of the B cell co-receptor complex, enhancing B cell activation by binding C3d and lowering the antigen concentration required for effective activation.

Summary of Key Concepts

• C3b forms bonds with antigens irrespective of its breakdown products, aiding in B cell activation through simultaneous binding with C3d and B-cell receptor.