3 Complement and cytokines pt 1

What is a complement system and its main roles?

→ major immune defense system of the body that’s central to the development of inflammatory reactions

• link the innate and adaptive arms of the immune system

• label pathogens for elimination

• form lytic transmembrane pores to destroy target cells

How do complement components interact with each other?

→ interact via a series of highly regulated proteolytic cascades

• many of these components are proenzymes that must be cleaved to become active enzymes

What are the components of complement system?

• serum

• membrane-bound proteins

Give the reaction sequence of the complement system.

 C1-C4-C2-C3-C5-C6-C7-C8-C9

List the 4 major biological effects of complement.

1. Priming of adaptive immune response

2. Opsonization

3. Chemotaxis and cell activation

4. Lysis of target cells

What is cytolysis? How does it occur?

→ lysis of cells (e.g., bacteria, tumor cells, or virus-infected cells)

• occurs via the formation of the Membrane Attack Complex (MAC)

  • made of complement proteins = C5b, 6, 7, 8, 9

• inserts into the cell membrane → makes a pore → loss of osmotic integrity → cell lysis → allows free water to freely pass across the membrane

What is chemotaxis? Give an example of a chemotactic protein and its role.

→ process where an immune cell (phagocyte) is attracted to and moves toward a soluble factor

• e.g., C5a is a potent chemotactic agent that stimulates neutrophils and monocytes to move toward sites where antigens are deposited

What is opsonization? How is phagocytosis efficiency increased?

→ coating of microorganisms or antigen-antibody complexes with molecules that bind to receptors on phagocytes

• Phagocytosis becomes more efficient in the presence of C3b b/c phagocytes have specific C3b receptors

What are anaphylatoxins? Provide examples and their roles.

→ complement fragments that promote:

• vasodilation

• ↑ vascular permeability

• promote adhesion & chemotaxis of neutrophils & monocytes

• e.g., C3a & C5a - stimulate mast cells & basophils → release vasoactive amines (histamine) → ↑ blood flow to the infection site → allows more immune components to enter

Give the 6 major roles of complement in inflammation.

1. Lysis (of bacteria)

2. Opsonization

3. Chemotaxis

4. Activation (of mast cells)

5. Degranulation (of mast cells)

6. Immune complex clearance

Name the 3 major complement pathways.

1. Classical pathway

2. Alternative pathway

3. Mannan-binding lectin (MBL) pathway

What do all 3 of these complement pathways release (Classical, Alternative & Mannan-binding lectin (MBL))?

C5 convertase - breaks down C5 into C5a + C5b

What is the role of C5a?

• anaphylatoxin

• chemotactic factor

What are the events following formation of C5b leading to the formation of MAC?

1. C5b binds with C6 + C7 → form a complex complex that inserts into the membrane bilayer

2. C8 then binds to this complex

3. Polymerization of 16 C9 to produce the complete MAC

Describe briefly the sequence of reaction and products formed during classical pathway.

1. C1 (q, r, s proteins) binds to the F_c region of an antibody (IgM or IgG) in an immune complex

2. This activates C1s

3. C1s cleaves C4 & C2 → C4b2b (active C3 convertase)

4. C4b2b cleaves C3 → C3a + C3b

5. C3b + C4b2b form C5 convertase

6. C5 convertase cleaves C5 → C5a + C5b

7. MAC formation → cell lysis

Which IgG subclass fix complement? IgG4 does not

1, 2, 3

❌ 4

What is the Alternative pathway?

• triggered directly by infectious agents

• uses different components like Factors B, D, and Properdin to generate its C3 convertase (C3bBb)

  • C3bBb makes more C3b, where additional C3b binds to the C3

    convertase to form C3bBbC3b

What does C3bBbC3b do?

Alternative pathway of C5 convertase that makes C5b → MAC production + cell lysis

What is the main constituent of the Mannan-Binding Lectin Pathway?

→ plasma protein MBL

• binds to sugar residues (mannose) on microbial LPS

• once bound it can activate C2 & C4

• remaining steps are the same as the classic pathway

Name the main microorganisms activating classical, alternative and lectin pathways.

Classical:

• HIV, retroviruses, vesicular stomatitis virus

• Mycoplasma spp.

Alternative:

• virus-infected cells (e.g., EBV),

• Gram (+) & (-) bacteria

• trypanosomes

• Leishmania spp

• fungi

Lectin:

• HIV, retroviruses

• Gram (+) & (-) bacteria