Immune responses against extracellular pathogens

Question 1

what are all the first barrier to infection

Answer 1

Physical barrier - tight junctions, desmosomes ,gap junctions

Mechanical barriers - fluids flow (sweat, tears mucus, urine) and normal flora

Chemical barriers- enzymes, lactoferrin, mucin, HCL, fatty acids and defensins

Question 2

How does human microbiome contributes towards immune system

Answer 2

The surfaces of this system
are covered with commensal flora which creates a naturally competitive environment. The
bacteria within the microbiome can secrete antimicrobial peptides known as bacteriocins or
can cause opportunistic infections in immunocompromised individuals.

Question 3

what are the two immunologically distinct regions of the gut

Answer 3

inductive sites/ peyer’s patches and effector sites

Question 4

What happens inside the Peyers patches

Answer 4

egions rich with naïve resting immune cells
• Sample microbes in the lumen of gut pass them onto macropahges and B cells to promote IgA responses against these pathogens
• DCs also sample other antigens including food to ensure immune tolerance for non-hazardous gut-content
• M cells transcytose material across the epithelial barrier and DCs can extend dendrites between epithelial cells to sample antigens
□ And induce tolerogenic activation of the immune system
• The DCs traffic to T-cell zones within the patch and activate Treg cells
• Treg cells migrate to the lamina propria and secrete IL-10 which suppresses the immune cells and epithelial cells to maintain immune quiescence.

Question 5

What is in the effector site

Answer 5

• Crammed with activated effector cells 
				□ plasma cells that secrete IgA and IgM
				□ Memory B cells 
				□ T helper cells 
				□ APCs

Question 6

How can complements target bacteria

Answer 6

Gram positive bactera have single membrane surrounded by thick wall of peptidoglycan hence cannot be target by MAC but can be target by opsonisation and anaphylotoxins which recruits phagocytes.

Gram negative can be targeted by both MAC and opsonisation

Question 7

Compare avidity of IgM

Answer 7

Each complentarity determining region binds weakly to antigen.
IgM pentamers has 10 CDRs and avidity is 10 times of affinity so low affinity antibodies can activate pathway

Question 8

How does bacteria avoid complement recognition

Answer 8

• Haemophilus infleunzae excretes protease enzyme able to accerlerate breakdown of complement proteins
• Staphylococcus aureus makes capsules that make bacterium more resistant to opsonisation by complement and secrete bacterial protein
○ Stimulates production of C3b-fibrinogen complexes to make opsonised decoy

Question 9

What diseases are caused by genetic defects in complement components

Answer 9

1. Deficiencies in early components of alternative pathway (eg. Factor D, Factor P, C3)
   • Known to lead to susceptibility to extracellular pathogens
   • Particularly to pyogenic bacteria
   • Which cause purulent (pus-forming) inflammation
   
   2. Deficiencies of Lectin pathway
      • Associated with early childhood susceptibility to infections
   3. MAC deficiencies
      ○ Lead to infection and susceptibility to Neisseria gonorrhoeae species

Question 10

How does neutrophils act on bacteria

Answer 10

they trap bacteria forming neutrophil extracellular traps (NETs) made of neutrophil DNA, histones and granule enzymes. NEt is coated in antimicrobial agents including myeoloperoxidase, neutrophil elastase and defensins. The neutrophil secretes PAD4 which allow chromosomal DNA to uncoil and are ejected from cell
NETs are degraded by serum nucleases and phagocytosed

Question 11

compare the sturcture of MHC class I and II

Answer 11

MHC molecules
consist of a cleft made of a-helices and a floor of b-sheets. The
peptide binding site on MHC II is made up of both a and b chains
whereas in MHC I, it is only made up of the a chains. Amino acid
side chains from the a and b chains contribute to the binding of
the antigenic fragment. MHC II peptides are 14-24 amino acids
long while MHC I peptides are only 7-11 long

Question 12

how is antigen loaded onto MHC

Answer 12

1. MHC II is assembled in the ER and has an invariant chain which binds to the cleft and prevents peptides in the ER from binding.
   
   2. Invariant chain guides transport of the MHC II into a vesicle which gradually acidifies, activates proteases and degrades most of the invariant chain.
   3. A peptide known as CLIP remains in the cleft of the MHC II which is removed by an MHC II–like molecule known as HLADM which catalyses the release of CLIP and the binding of pathogenic antigens
   4. The vesicle then fuses with the plasma membrane and MHC II presents its antigen to TH cells.

Question 13

What proteasome is used to digest pathogens and produce peptides for MHC

Answer 13

immunoproteasome

Question 14

What happens when MHC present self-antigens

Answer 14

clonal section in thymus which deletes T cells whose receptors can bind to self peptides on MHC molecules

Question 15

How can bacteria activate inflamamtory response

Answer 15

they produce endotoxin and exotoxin

Question 16

How does bacteria defend themselves from being detected by MHC class II presentation pathway

Answer 16

gram-positive bacteria secrete exogenous superantigens that cause non-specific activation of T cells, inducing overactivity of immune response

Question 17

Action of superantigen

Answer 17

• Superantigen binds to outside of MHC Class II and joins to variable domain (Vβ) of T cell receptor
○ Binding allow coreceptors to crosslink and signal to T cell that it has found the enemy
○ -> lead to overproduction of pro-inflammatory cytokines (such as TNF-a and IL-2) by T helper cells
• Leading to systemic toxicity
• Superantigen has caused this activation independent of the peptide
○ indiscriminate activation of non-specific T cells, helping the bacterium to overwhelm any specific responses there might be
• organism has less chance of developing an effective T cell memory response
○ likely to be a mixed in with a much larger number of non-specific T cells
○ overstimulate existing memory T cells, causing them to become ‘exhausted’ (the state ofanergy) and thus ineffective, or even tolerant for their target.

Question 18

Can B cell activate without T cell

Answer 18

Yes, If enough antibodies bind to the antigen,
the B cell can become activated without T-cell help. The Fc region of the B-cell binds the Fc
receptor on the APC, to internalise the antigens presented on MHC II.

Question 19

Action of antibodies

Answer 19

opsonisation - by bind to target so they can internalise the antigen for MHC class II presentation 
neutralisation - where antibody binds to pathogen protein and block its function

Question 20

How can bacteria avoid antibodies

Answer 20

antigenic variation which shuffles the genes

encoding bacterial surface proteins that would not be recognized by antibodies from previous infection