Complement and Cytokines

Question 1

What is the complement system?

Answer 1

• Helps other parts of the immune system

- Non-cellular, comprising of a cascade of 9 major serum proteins

Question 2

What are the roles of the complement system?

Answer 2

1. Initiate inflammation and cell degranulation
2. Attracts neutrophils to infection site
3. Oponisation
4. Attacks membranes
5. Agglutination
6. Clearance of immune complexes/cell debris

Question 3

What is the most common pathway by which complement is activated?

Answer 3

• Pathogen surface markers/antigen-antibody complex/mannose binding lectin activates C3 through enzymes convertases
• generates C3a and C3b
• initiates major effector outcome

Question 4

What is the structure of the clasical pathway cytokine C1?

Answer 4

Composed of subunits C1q, C1r and C1s which are bound by collagen

Question 5

How is C1 activated?

Answer 5

Encounters antibody-antigen complex (IgG/IgN) which attach to Fc region bringing about agglutination, exposing enzymatic site (C1q) which acts on serum protein C4 to cleave it into C4a and C4b

Question 6

How do C4a and C4b further initiate the immune response (classical pathway)?

Answer 6

• C4b sticks to cell pathogen surface acting as a binding site for C2 which anchors it to the cell surface
• Enzymatic site exposed cleaving C2 into C2a and C2b
• C4b combines with C2a becoming a heterodimer with exposed cleavage site on C2a
• C3 binds temporarily and cleaved into fragments C3a and C3b

Question 7

How does the lectin pathway differ from the classical pathway?

Answer 7

• Lectin involved in activation is specific to mannose

- Hexamer bound to 2 pairs of serine proteases at N terminus : MASP1 & MASP2 which cleaves C4 in serum

Question 8

How is the alternative pathway activated?

Answer 8

• Continuous low-level hydrolysis of C3 from water in body fluids causes cleavage of thioester bond
• Microbe binds to factor B in presence of Mg causing formation of C3bB complex

Question 9

How does the C3bB complex (alternate pathway) go on to act on the immune system?

Answer 9

• Attacked by factor D cleaving off Ba
• Cleaved C3b has exposed thioester site which can bidn to pathogen/immune cell, bind to C4bC2a (convertase for C5) or hydrolyse tissue in fluid
• outcome depends on environment, binding affinities and the ammount of C3b

Question 10

How do C3b and C4b act on opsonisation?

Answer 10

• Both bind directly to microbe
• Bind to specific receptors on a phagocyte resulting in uptake
• C4b enhances C3b mediated opsoniation

Question 11

Which 3 ways can C5 convertase be generated?

Answer 11

C4bC2aC3b - classical pathway
C4bC2aC3b - lectin pathway
C3bBb - alternate pathway

Question 12

What does the activation of C5 result in?

Answer 12

• Cleaved into C5a and C5b
• C5b binds sequentially to C6, C7, C8 and 12*C9 molecules to form a complex that inserts into cell membrane allowing the inrush of fluids

Question 13

What other effects can the components of the C5 pathway have?

Answer 13

C3a +C5a - degranulation of immune cells
C4b - agglutinates and neutralises virus
C5a - recruitment od neutrophils/macrophages
Bb - Aids in proliferation of active B cells
Ba - Inhibits proliferation of active lymphocytes

Question 14

What are cytokines?

Answer 14

Small soluble peptides, proteins or glycoproteins acting as signals which bind to specific cell surface receptors

Question 15

What are the main functions of cytokines?

Answer 15

• Promoting and regulating inflammation
• Adaptive response to infection
• Haemopoeisis, leucocyte growth and development

Question 16

What are the 3 main features of cytokines?

Answer 16

Pleitropic: act on different cell types
Redundant: different cytokines carry out the same function
Multifunctional: able to regulate a number of different processes

Question 17

What are the main cytokine groups? Give examples

Answer 17

monkines - released by monocytes and macrophages (IL-1, IL-6 and TNFalpha)
chemokines - chemotaxins produced following infection or damage (IL-8)
interferons - inhibit viral replication, increase NK activity (IFNalpha/beta/theta)
lymphokines - lymphocyte growth factors (IL-2, Il-3, IL-4)
others - nuch as tumor necrosis factor which is cytotoxic to other cells

Question 18

Which cytokines are pro-inflammatory?

Answer 18

INFtheta, TNFalpha, IL-2, IL-6, IL-12

Question 19

Which cytokines are anti-inflammatory?

Answer 19

IL-4, IL-13, IL-10 and TGF

Question 20

How to cytokines play an important role in adaptive immunity?

Answer 20

• Th cells produce cytokines IL-2, TNfalpha, IFNtheta as a consequence of CD4+ binding to MHC II which play a role in the generation of Tc cells
• Th cells also produce IL-4, IL-10 and IL-13 which are important for B cell differentiation and stimulate anti-parasitic defence by stimulating IgE production

Question 21

What cells produce the cytokine TNF alpha and what does it target?

Answer 21

• Produced by macrophages, dendritic cells and mast cells

- Targets lymphocytes, endothelial cells, the liver and the CNS

Question 22

What are the effects of TNF alpha?

Answer 22

• Activates APCs, causes pyrexia (fever) and cauchexia (wasting)
• Enhances MHC I production
• Inhibits tumourgenesis
• Enhances lymphocyte and endothelial cell adhesion
• Stimulates IL-1, IL-6 and IL-8 release
• Activates t-reg cells

Question 23

What role does INF theta play in immunity?

Answer 23

• Produced by NK cells, Tc and macrophages
• Promotes NK activity and increases antigen presentation
• Promotes Th differentiation
• Causes cells to present MHC I
• Promotes leucocyte binding

Question 24

How does interferon produce antiviral activity?

Answer 24

• Virus infected cell produces INF which binds to receptors on neighbouring cells of the same type
• These cells are induced to produce enzymes that degrade mRNA, preventing viral protein synthesis and halting its spread