30. Immune Response

Question 1

Describe the innate immune system giving an overview, its features, functions and perceptive points.

Answer 1

The innate immune system is a collection of cells and molecules that detect pathogens upon initial entry in host tissues (after breaching epithelial barriers) and co-ordinate the inactivation/killing of the pathogen. The innate immune system is the first line of defence against inactivaiton before activation of the adaptive immune system

Features of the innate immune system:

• Fast acting (from pathogen entry to 4 days)
  
  • The IIS is fast, acting on the timescale of hours to days (up to 4 days). This is important in defence against the early stages of infection because the powerful adaptive immune response requires a long time to develop due to the clonal expansion of B and T lymphocytes
• Broad specificity
  
  • Recognises molecular patterns that are common to groups of pathogens /conserved among pathogens. Same immune mechanisms target multiple pathogens
  • The system is described as “innate” because the proteins involved are encoded entirely by inherited genes (germ-line encoded) - no gene rearrnagement to produce varriable protein strcutures as in AIS

The functions of innate immune response (IRR) are:

• The inactivation of pathogens durign the early stages of infection
• Activation of the acquired immune system to generate long-lasting immunity (antigen presentation, dendritic cells etc.)

Perceptive points

• The AIS is old and evolutionarily conserved, even plants have an IS.
• It is germline encoded
• Rapid & non-specific

Question 2

Answer 2

Question 3

What are the barriers to infection that prevent pathogen entry and immune activation?

Answer 3

• Physical barriers
  
  • ​Skin
  • Mucosal surfaces
• ​Chemical barriers
  
  • ​Stomach acid​​
    
    • Proton pump inhibitors (PPI) increase risk of GI infections ​

Question 4

What are pathogen associated molecular patterns (PAMPs?)

Answer 4

• Expressed by pathogens (such as bacterial cell wall componentns and viral nucleic acids)
• They are detected by pattern recognition receptors (PRRs) of the innate immune system found in the ECF, on cell surfaces and inside cells (e.g. macrophages, neutrophils, dendritic cells)
• PAMPs exhibit molecular structures that are not present on human cells thus the evolutrion of PRRs that bind specifically to PAMPs enables the distinction between self and non-self material
• There is a diversity of PRRs that enable the detection of a wide range of PAMPs and thus a large number of different pathogens
• Recognition mechanisms are importnat in distinguishing between self and non-self material thus protectign host cells from excessive damage
• DAMPs released from damaged infected cells can perpetuate the effects of PAMPs on the immune system through the activation of lipid mediators such as leukotrienes

Question 5

What is the complement system?

Answer 5

• The complement system is a system of 31 heat labile, soluble proteins circulating in the extracellular fluids (blood, lymph and interstiial fluid) that are activated upon the detection of pathogens and mediate their direct killing or marking for destruction by other cells
  
  • Thus they are both afferent and efferent in their functions
• Complement proteins are recognised and released by the liver
• Many complement proteins are serine proteases that normally assume an inactive zymogen form and are activated in a cascade of proteolytic cleavage where one enzyme cleaves and activates the downstream enzyme

Question 6

Draw out the complement cascade

Answer 6

Question 7

What is the key event in the complement system? What does it result in?

Answer 7

• The cleavage of C3 to C3a and C3b (C3b is the most importnat component)
• C3b remains attached (covalently bound) to the pathogen surface known as complement fixation
  
  • The bound C3b coordiantes complement effector mechanisms resulting in the cleavage of C5 into C5A and C5b and further n the formation of the membrane attack complex (MAC)

Question 8

Which pathway of the complement system is the first to be activated? Outline its pathway

Answer 8

• The alternative pathway (one of the first innate immune responses especially to bacterial infection)
• It is the most importnat pathway because it does not rely on the detection of pathogens by cells for its activation and can therefore act rapidly
• Pathway (forms a fluid-phase C3 convertase)
  
  • In the plasma close to a pathogen surface, the thioester bond of C3 is spontaneously hydrolyzed, producing iC3 [C3(H₂O)] (local conditions promote hydrolysis)
  • iC3 binds to factor B which is then cleaved by factor D to produce Ba and Bb
  • Bb remains bound to iC3 to form the C3 convertase iC3Bb which binds C3 and cleaves it to C3a and C3b (in solution)
  • This initiates a positive feedback loop in which fixed C3b forms C3bBb and cleaves more C3, amplifying the initial signal and rapidly coating the pathogen with C3b

Question 9

Outlin the lectin pathway.

Answer 9

• Stimulus
  
  • Mannose-binding lectin (MBL) circulates in the plasma as a complex with the MBL associated serine proteases MASP-1 and MASP-2
  • The recongition of mannose residues in pathogen carboydrates by MBL results in attachment of the complex to the pathogen surface and provokes cleavage of MASP-2
• ​Pathway
  
  • The activated MASP-2 protease cleaves C4 producing C4a and C4b, the letter of which attaches to the pathogen surface
  • MASP-2 also cleaves C2 to form C2a and C2b
  • ​C2a binds to C4b on the pathogen surface forming the classical C3 convertase C4bC2a
  • C4bC2a cleaves C3 generating C3b which attaches to the pathogen and catalyses the assembly of the alterantive C3 convertase C3bBb via the mechanisms described in the alternative pathway
    
    • This is the point where all the complement pathways converge
• Notably, the alternative C3 convertase fixes more C3b than the classical convertase because the plasma {C3] is higher than [C4]

Question 10

Describe the MBL deficinecy?

Answer 10

• Inactivating mutations in MBL increase susceptibiity to infection by Neisseria meningitidis

Question 11

• Outline the classical pathway

Answer 11

• Stimulus
  
  • C-reactive protein (CRP) in the plasma binds to a number of recognition molecules on pathogens such as:
    
    • Phospocholine in bacterial lipopolysaccharides (LPS)
    • Antigen-antibody complexes (IgM or IgG) generates by theacquired immune system
• Pathway
  
  • CRP binds C1, a complex of C1q, C1r and C1s that resembles the MBL/MASP complex
  • This promotes the cleavage of C1r which then cleaves C1s to form an active C1s protease
  • C1s cleaves C4 and C2 generating the classical convertase C4bC2a and thus converging on the lectin and alternative pathways

Question 12

Compare and contrast the three complement systems.

Answer 12

• The different pathways are activated in response to different pathogenic markers, the alternative pathway is activated in the innate immune response as it does not require direct activation by the pathogen.
  
  • C3 is spontaneously converted into iC3 near the pathogen surface.
  • iC3 is cleaved by factor D to form an active C3 convertase that mediates C3a and C3b formation
• As the infection develops, the classical and lectin pathways are activated
• The classical pathway is activated by CRP (C-reactive protein) whereas the lectin pathway is activated by mannose-binding protein (MBP) made in the liver during the acute phase response to infalmmatory cytokines
• MBL recognizes mannose on pathogen carbohydrates whereas CRP binds to phosphocholine in bacterial LPS and antigen-antibody complexes (IgG or IgM) generated by the adaptive immune system (AIS)
• MBL and CRP are reacted with other complement proteins to form an active C3 convertase (C4b2a)