Immune responses against extracellular pathogens Flashcards
what are all the first barrier to infection
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
How does human microbiome contributes towards immune system
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.
what are the two immunologically distinct regions of the gut
inductive sites/ peyer’s patches and effector sites
What happens inside the Peyers patches
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.
What is in the effector site
• Crammed with activated effector cells □ plasma cells that secrete IgA and IgM □ Memory B cells □ T helper cells □ APCs
How can complements target bacteria
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
Compare avidity of IgM
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
How does bacteria avoid complement recognition
• 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
What diseases are caused by genetic defects in complement components
- 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- Deficiencies of Lectin pathway
• Associated with early childhood susceptibility to infections - MAC deficiencies
○ Lead to infection and susceptibility to Neisseria gonorrhoeae species
- Deficiencies of Lectin pathway
How does neutrophils act on bacteria
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
compare the sturcture of MHC class I and II
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
how is antigen loaded onto MHC
- 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.
- Invariant chain guides transport of the MHC II into a vesicle which gradually acidifies, activates proteases and degrades most of the invariant chain.
- 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
- The vesicle then fuses with the plasma membrane and MHC II presents its antigen to TH cells.
What proteasome is used to digest pathogens and produce peptides for MHC
immunoproteasome
What happens when MHC present self-antigens
clonal section in thymus which deletes T cells whose receptors can bind to self peptides on MHC molecules
How can bacteria activate inflamamtory response
they produce endotoxin and exotoxin
How does bacteria defend themselves from being detected by MHC class II presentation pathway
gram-positive bacteria secrete exogenous superantigens that cause non-specific activation of T cells, inducing overactivity of immune response
Action of superantigen
• 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.
Can B cell activate without T cell
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.
Action of antibodies
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
How can bacteria avoid antibodies
antigenic variation which shuffles the genes
encoding bacterial surface proteins that would not be recognized by antibodies from previous infection
